Mercaptosulfide metalloproteinase inhibitors

ABSTRACT

Novel mercaptosulfide matrix metalloproteinase inhibitors of the Formula I, ##STR1## wherein: n is 0 or 1; 
     R 1  is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); and 
     R 2  is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH (lower alkyl); or 
     R 1  and R 2  together are --CH 2  --CH 2  --CH 2  --; 
     R 3  is selected from the group consisting of hydrogen, lower alkyl, aralkyl and heteroaralkyl; and 
     R 4  is selected from the group consisting of hydrogen, lower alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, aralkyl and 2-indolylmethyl; and 
     R 5  is selected from the group consisting of lower alkyl, aralkyl and --CH(R 6 )--C(O)NH 2 , 
     wherein 
     R 6  is selected from the group consisting of hydrogen, lower-alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, hydroxymethyl, 1-hydroxyethyl, mercapto lower-alkyl, and methylthio lower-alkyl; or 
     a pharmaceutically acceptable ester, ether or salt thereof, useful for treating diseases and disease conditions associated with matrix metalloproteinase modulation.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to pharmaceutically active mercaptosulfide derivatized peptides useful as inhibitors of the matrix metalloproteinase (MMP) family of enzymes for use in modulating physiological functions or treating diseases and disease conditions associated with MMP modulation, for example: arthritic diseases, such as osteoarthritis (OA), rheumatoid arthritis (RA), septic arthritis, soft tissue rheumatism, polychondritis and tendonitis; tumor invasion in certain cancers; periodontal diseases; corneal ulceration, e.g., that induced by alkali or other burns, by radiation, by vitamin E or retinoid deficiency; glomerular diseases, such as proteinuria, dytrophobic epidermolysis bullosa; bone resorption diseases, such as osteoporosis, Paget's disease, hyperparathyroidism and cholesteatoma; birth control through preventing ovulation or implantation; angiogenesis relating to tumor growth or to the neovascularization associated with diabetic retinopathy and macular degeneration; coronary thrombosis associated with atherosclerotic plaque rupture; and pulmonary emphysema. In addition to the compounds and their use, the invention also relates to their precursors, to their preparation and to pharmaceutical compositions using the compounds of the invention.

2. Background Information

The MMPs are a family of zinc-containing proteinases believed to be responsible for the metabolic turnover of protein components of the extracellular matrix of humans. At present there are at least eight known human MMP.

Various disease and disease conditions have been linked with the actions or presence of MMP, e.g., elevated levels of certain of these enzymes exists in joints of arthritic humans and animals and therefore have been linked to the degradation of the major components of articular cartilage and basement membranes. It is presently believed that the collective action of the MMP on extracellular matrix macromolecules is responsible for the destruction of connective tissue, however, the precise role of each enzyme in the process is not yet well understood. It has also been reported that certain MMP may be instrumental in mediating certain normal physiological functions that involve the breakdown or development of tissue.

It has been desired to selectively inhibit certain MMP enzymes, specifically those which modulate certain diseases, physiological conditions and disease conditions, in order that such conditions could be controlled.

It has been surprisingly discovered that a family of mercaptosulfide derivatized polypeptides are potent inhibitors of MMP, thereby affording a method of treating MMP-mediated diseases and disease conditions, and controlling MMP-mediated physiological functions.

SUMMARY OF THE INVENTION

Novel mercaptosulfide matrix metalloproteinase inhibitors of the Formula I, ##STR2## wherein: n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH-(lower alkyl); and

R² is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH-(lower alkyl); or

R¹ and R² together are --CH₂ --CH₂ --CH₂ --;

R³ is selected from the group consisting of hydrogen, lower alkyl, aralkyl and heteroaralkyl; and

R⁴ is selected from the group consisting of hydrogen, lower alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, aralkyl and 2-indolylmethyl; and

R⁵ is selected from the group consisting of lower alkyl, aralkyl and --CH(R⁶)--C(O)NH₂,

wherein

R⁶ is selected from the group consisting of hydrogen, lower-alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, hydroxymethyl, 1-hydroxyethyl, mercapto lower-alkyl, and methylthio lower-alkyl;

or a pharmaceutically acceptable ester, ether or salt thereof, useful for treating diseases and disease conditions associated with MMP modulation, e.g., arthritic diseases, such as osteoarthritis (OA), rheumatoid arthritis (RA), septic arthritis, soft tissue rheumatism, polychondritis and tendonitis; tumor invasion in certain cancers, periodontal diseases; corneal ulceration, e.g., that induced by alkali or other burns, by radiation, by vitamin E or retinoid deficiency; ulceration of the skin and gastrointestinal tract, and abnormal wound healing; post operative conditions, including colonic anastomosis; glomerular diseases, such as proteinuria, dytrophobic epidermolysis bullosa; bone resorption diseases, such as osteoporosis, Paget's disease, hyperparathyroidism and cholesteatoma; birth control through preventing ovulation or implantation; demyelinating diseases of the central and peripheral nervous systems, including syndromes in which myelin loss is the primary pathological event and those in which demyelination follows axonal atrophy, e.g., multiple sclerosis, angiogenesis relating to tumor growth on to the neovascularization associated with diabetic retinopathy and macular degeneration; and coronary thrombosis associated with atherosclerotic plaque rupture.

DETAILED DESCRIPTION Definitions and General Parameters

The term "alkyl" refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms.

The term "lower-alkyl" refers to a branched or straight chain monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, propyl, isopropyl, butyl (e.g., isobutyl, t-butyl, or n-butyl), pentyl, and hexyl.

The term "aryl" refers to an aromatic monovalent carbocyclic radical, which can optionally be mono-, di-, tri- or tetra-substituted, independently, with lower alkyl (e.g., methylphenyl, ethylphenyl), lower-alkyoxy (e.g., 4-methoxyphenyl), hydroxy (e.g., 4-hydroxyphenyl) halo, carboxy, lower-alkoxycarbonyl, carbamoyl, mono- and dimethylcarbamoyl, lower-alkyl carbonyl (such as, methylcarbonyl and ethylcarbonyl), hydroxymethyl, amino, trifluoromethyl, cyano or nitro.

The term "aralkyl" refers to the group (aryl)-(lower-alkyl)-. For example, typical aralkyl groups are e.g., phenylmethyl (i.e., benzyl), phenylethyl, 4-hydroxyphenylmethyl, or 4-methoxyphenylmethyl.

The term "heteroaryl" refers to aromatic monovalent mono- or bi-carbocyclic radical having at least one heteroatom, i.e., nitrogen, oxygen or sulfur, which can optionally be mono- or di-substituted adjacent to the heteroatom, independently, with lower alkyl, halo, cyano, amino or trifluoromethyl. For example, typical heteroaryl groups with one or more nitrogen atoms are tetrazoyl, pyridyl (e.g., 4-pyridyl, 3-pyridyl, 2-pyridyl), 2-indolyl, 3-indolyl, pyridazinyl, quinolinyl, 2-quinolinyl, 3-quinolinyl, imidazolyl, isoquinolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridonyl or pyridazinonyl; typical oxygen heteroaryl radicals with oxygen atom are furanyl, or benzofuranyl; typical sulfur heteroaryl radicals are thienyl, and benzothiophenyl.

The term "heteroaralkyl" refers to the group (heteroaryl)-(lower alkyl). For example, typical heteroaralkyl groups are e.g., imidazoyl lower-alkyl, such as, 4-imidazolylmethyl, 3-imidazolylmethyl, 4-imidazoylethyl, or indolyl lower-alkyl, such as, 2-indolylmethyl, 3-indolylmethyl,

The term "guanyl" refers to the moiety carbamimidoylamino ##STR3##

The term "PhtN" refers to ##STR4## i.e., phthalimido moiety.

The term "PhtN ( lower alkyl )" refers to ##STR5## e.g., PhtNBu (i.e., 4-phthalimidobutyl) or PhtNEt (i.e., 2-phthalimidoethyl).

The term "PheNHMe" refers to ##STR6##

The term "TrpNHMe" refers to ##STR7##

The term "Phe-Ala-OH" refers to ##STR8## The term "TsNH-(lower alkyl)" refers to ##STR9## e.g., 4-(p-toluenesulfonamido)-butyl.

The term "blocking group" or "BG" refer to a chemical group which exhibits the following characteristics. The group must react selectively in good yield to give a blocked or protected substrate that is stable to the projected reactions; and the blocking group must be selectively removable in good yield by readily available, preferably nontoxic reagents that do not attack the functional group(s) generated in such projected reactions. For example, typical blocking groups are benzyloxycarbonyl, tert-butyldimethylsilyl, or benzyl [for additional blocking or protecting groups see "Protective Groups", J. F. W. McOmie, Adv. Org. Chem., 3, 191 (1963) or "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wilts, John Wiley & Sons, 2nd Edition, 1991] are used for protecting substrates containing the chemical moieties, such as 4-hydroxyphenylmethyl, 3-indolylmethyl, 4-aminobutyl, 3-guanylpropyl or 4-imidazoylmethyl.

The term "blocked" refers to a chemical moiety that has been treated with a blocking group.

The term "de-blocking" reagent refers to a reagent which is used to remove a blocking group, e.g., elemental Na and liquid ammonia for debenzylation of S-benzyl (Evans, D. A.; Mathre, D. J.; Scott, W. L. J. Org. Chem. 1985, 50, 1830-1835), 10% Pd/C with catalytic amount of cyclohexylamine and H₂ gas for removing CBz from imine moiety, or tetrabutylammonium fluoride hydrate for remove t-butyldimethylsilyl moiety.

"Enantiomers" are two stereoisomers whose molecules are non-superimposable mirror images of one another.

"Diastereoisomers" or "diastereomers" are stereoisomers with two or more centers of asymmetry and whose molecules are not mirror images of one another.

The term "racemic" means existing as a racemate, or as a 50--50 mixture of two enantiomers, also denoted by "d1" or "±".

The terms "D" and/or "L" refers to the absolute configuration at an asymmetric carbon of a molecule assigned according to experimental chemical correlation with that of the α-carbon of a modified or unmodified amino acid residue (using the absolute configuration of the α-carbon of D- or L-serine as the standard).

The designation "DL" indicates a mixture of the D and L stereoisomers or that diastereomers were separated but not identified.

Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, preparative high pressure liquid chromatography (preparative HPLC), thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

Nomenclature

The following convention of abbreviations and nomenclature has been adopted and will be used to name the compounds of the present invention.

Common naturally occurring amino acids relating to the present invention are listed below in tables according to their radical type (e.g., aliphatic, aromatic, basic or substituted aliphatic).

    ______________________________________                                                     Radical       Abbreviation                                         ______________________________________                                         Aliphatic Amino Acids                                                          Glycine       H               Gly                                              Alanine       methyl          Ala                                              Val           2-propyl        Val                                              Leucine       2-methylpropyl  Leu                                              Isoleucine    2-butyl         Ile                                              Aromatic Amino Acids                                                           Phenylalanine benzyl          Phe                                              Tyrosine      4-hydroxyphenylmethyl                                                                          Tyr                                              Tryptophan    3-indolylmethyl Trp                                              Basic Amino Acids                                                              Lysine        4-aminobutyl    Lys                                              Arginine      3-guanylpropyl  Arg                                              Histidine     4-imidazoylmethyl                                                                              His                                              Substituted Amino Acids                                                        Cysteine      thiolmethyl     Cys                                              Methionine    methylthioethyl Met                                              Serine        hydroxymethyl   Ser                                              Threonine     1-hydroxyethyl  Thr                                              ______________________________________                                    

The abbreviation "Ac-" refers to the acetyl radical.

The abbreviation "Bn-" or "Bnz-" refers to the benzyl radical (i.e., phenylmethyl).

The abbreviation "AcS-" refers to the thiolacetyl radical.

The abbreviation "-OEt" refers the ethoxy radical.

The abbreviation "RS-" refers to a lower-alkyl sulfide radical.

The abbreviation "BnS-" refers to the benzylsulfide radical.

The abbreviation "TBS" refers to the tert-butyldimethylsilyl radical.

The abbreviation "Cbz" refers to the benzyloxycarbonyl radical, i.e., ##STR10##

The abbreviation "(Phet)" refers to the modified amino acid with phenylethyl as the radical, i.e., ##STR11##

The abbreviation "(Tyr-OCH₃)" refers to the modified amino acid with 4-methoxyphenylmethyl as the radical, i.e., ##STR12##

Certain naming conventions are accepted to represent the structure of modified peptides. For example,

a modification of the C═O group of an amino acid residue is signified by the usual three-letter code for the residue followed by the formula of the group that has replaced the C═O, separated by a hyphen, all enclosed in parentheses,

a modification of the NH group of a residue is analogously indicated by the three-letter code for the residue preceded by the formula of the group substituting for the NH, separated by a hyphen, all enclosed in parentheses, and

the stereoconfiguration of the α-carbon of a residue is indicated by the letters L or D preceding the three-letter code for the residue. The absence of either letters, or the presence of both letters indicates a mixture of the L and D isomers, or that diastereomers were separated but not identified.

Some representative compounds are named in the following examples.

For example, ##STR13## where n is 0, R¹ and R² are hydrogen, R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is --CH(R⁶)--C(O)NH₂ and R⁶ is methyland the carbon that is the point of attachment for R³ is in the D-configuration, is designated as HS(CH₂)₂ --(S-D-Leu)-Phe-NHMe.

For example, ##STR14## where n is 0, R¹ is methyl, R² is hydrogen, R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is --CH(R⁶)--C(O)NH₂ and R⁶ is methyl, and the carbon that is the point of attachment for R³ is in the D-configuration and the carbon that is the point of attachment for R¹ is in the S-configuration, is designated as HS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe.

For example, ##STR15## where n is 0, R¹ is hydrogen, R² is methyl, R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is --CH(R⁶)--C(O)NH₂ and R⁶ is methyl, and the carbon that is the point of attachment for R³ is in the D-configuration and the carbon that is the point of attachment for R¹ is in the R-configuration, is designated as HSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe.

For example, ##STR16## where n is 0, R¹ and R² are --CH₂ --CH₂ --CH₂ --, R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is --CH(R⁶)--C(O)NH₂ and R⁶ is methyl, and the carbon that is the point of attachment for R³ is in the D-configuration, is designated as HS-(1,2-cyclopentyl)-(S-D-Leu)-Phe-NHMe.

For example, ##STR17## where n is 1, R¹ and R² are --CH₂ --CH₂ --CH₂ --, R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is --CH(R⁶)--C(O)NH₂ and R⁶ is methyl, and the carbon that is the point of attachment for R³ is in the D-configuration, is designated as HS-(1,3-cyclohexyl)-(S-D-Leu)-Phe-NHMe.

Synthesis of the Compounds of Formula I

Reaction Scheme A describes the preparation of compounds of Formula I where R¹ and R² are the same substituent, and R³, R⁴, R⁵, R⁶ and R⁷ are the same as described in the Summary of the Invention.

Reaction Scheme B describes the preparation of compounds of Formula I where R² is hydrogen, n is 0, and R¹, R³, R⁴, R⁵, R⁶ and R⁷ are the same as described in the Summary of the Invention.

Reaction Scheme C describes the preparation of compounds of Formula I where R¹ is hydrogen, n is 0, and R², R³, R⁴, R⁵, R⁶ and R⁷ are the same as described in the Summary of the Invention.

The compounds described in Reaction Schemes A, B and C may contain single or multiple chiral centers and therefore may exist as enantiomers or diastereomers. It should be understood that unless otherwise indicated, the compounds described in Reaction Schemes A, B and C are intended to represent enantiomeric and/or diastereomeric mixtures, either racemic or non-racemic. The scope of the subject invention herein is considered to encompass all stereoisomers of the subject compounds and mixtures thereof.

REACTION SCHEME A Starting Materials

The compounds of Formula 1, i.e., amino acids (natural and modified) are commercially available from Aldrich Chemical Company or Sigma Chemical Company, or can be prepared following procedures known to those of ordinary skill in the art.

Preparation of Formula 2 ##STR18##

An amino acid or modified amino acid, i.e., a compound of Formula 1, is combined with about 3.5 molar equivalents of a halogen salt, such as, NaBr, KBr, NaCl, KCl, NaI, KI, preferably, KBr, and a strong acid, concentrated H₂ SO₄ (about 0.2 mL/molar equivalent) in water at a temperature in the range of about -10° C. to 0° C., preferably about -4° C. To this solution is added about 1.5 molar equivalents of a nitrosating reagent, such as, NaNO₂ over a period of about 1 hour. After completion of the addition, the reaction mixture is stirred for an additional 1 hour. The solution is extracted with a nonpolar organic solvent, e.g., methylene chloride. The organic layer is washed, dried and evaporated to yield the desired 2-halo-optionally substituted carboxylic acid, i.e., a compound of Formula 2.

Preparation of Formula 4 ##STR19##

About 14 molar equivalents of an optionally substituted lower-alkyl dimercapto compound (i.e., a compound of Formula 3 where R¹ and R² are the same) is combined with about 2.4 molar equivalents of Na in an alcoholic solvent, such as, ethanol, with stirring at about room temperature under an inert atmosphere. After stirring for about 10 minutes, a solution of 2-halo-optionally substituted carboxylic acid, i.e., compound of Formula 2, in an alcoholic solvent, such as, ethanol, is added. The reaction mixture is stirred at about room temperature for a period of about 12 to 20 hours, preferably about 16 hours. The reaction solution is poured into water, acidified and extracted with a nonpolar organic solvent, e.g., methylene chloride. The organic layer is dried, and the solvent and remaining dimercapto starting material is removed by vacuum. The residue is purified by flash chromatography, e.g., 15% ethyl acetate in hexane, to yield the desired mercapto 2-optionally substituted lower-alkyl sulfide carboxylic acid, i.e., a compound of Formula 4.

Preparation of Formula 5 ##STR20##

About 1 molar equivalent of a mercapto blocking agent, such as, benzamidomethanol (commercially available from Pfaltz and Bauer Chemical Companies) and a strong acid, such as, trifluoroacetic acid (about 2.3 mL/molar equivalent), is combined with a mercapto lower-alkyl thiocarboxylic acid, i.e., a compound of Formula 4, with stirring at a temperature in the range of about -10° C. to 10° C., preferably about 0° C. After completion of the addition, the mixture is stirred for about 1 hour. The acid and solvent are removed by vacuum, and the residue is purified by chromatography, e.g., silica gel to yield the desired blocked mercapto lower-alkyl thiocarboxylic acid residue, i.e., a compound of Formula 5.

Preparation of Formula 6 ##STR21##

A compound of Formula 6 is formed by the following procedure, which is a modification of procedures reported in Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis; Springer-Verlag: New York, 1984; p 129-142. A compound of Formula 6a (where R⁴ is hydrogen, lower-alkyl, blocked 4-aminobutyl, blocked 3-guanylpropyl, blocked 4-imidazoylmethyl, benzyl, blocked 4-hydroxyphenylmethyl, 3-indolylmethyl, 4-methoxyphenylmethyl or phenethyl) is combined with about 1 to 1.2 molar equivalents of N-hydroxysuccinimide, 1 to 1.2 molar equivalents of 1,3-dicyclohexylcarbodiimide and an anhydrous solvent (at about 1.2 mL/mmolar equivalent) such as tetrahydrofuran at a temperature in the range of about 0° C. to 10° C., preferably about 4° C. under an inert atmosphere for a period of about 13 to 39 hours, preferably about 26 hours. The resulting precipitate is removed by filtration. To the filtrate is added about 1.3 molar equivalents of a compound of Formula 6b dissolved in THF or in water, and if R⁵ is --CH(R⁶)--CO₂ H, 1.3 molar equivalents of a strong base such as sodium hydroxide in water is also added. The combined mixture is stirred at about room temperature for a period of about 12 to 24 hours, preferably about 18 hours. The solid residue is removed by filtration and the filtrate is diluted with saturated aqueous NaHCO₃ and is extracted with a non-polar solvent (e.g., CHCl₃). If R⁵ is lower-alkyl or aralkyl, the organic layer is evaporated to give the crude protected amino acid amide. If R⁵ is --CH(R⁶)--CO₂ H, the aqueous layer is acidified and the resulting precipitate is collected, washed and dried to yield the crude protected dipeptide acid. The crude protected dipeptide acid is subjected again to the above procedure, using excess anhydrous ammonia in an anhydrous solvent such as tetrahydrofuran, to give the crude protected dipeptide amide.

The crude protected amino acid amide or crude protected dipeptide amide from this procedure is subjected to hydrogenolysis in methanol over 10% Pd/C. The product is purified by flash chromatography (e.g., ethyl acetate-methanol, 10:1) to afford a compound of Formula 6.

Preparation of Formula 7 ##STR22##

About 1 molar equivalent of an amino acid, modified amino acid or peptide fragment (with a free N-terminus), i.e., a compound of Formula 6, is combined with a blocked mercapto lower-alkyl thiocarboxylic acid, i.e., a compound of Formula 5, in a solvent, such as, 1,2-dimethoxyethane with stirring at a temperature in the range of about 0° C. to 10° C., preferably about 5° C. To this solution is added a peptide coupling reagent, such as, about 1.2 molar equivalents of 1-hydroxybenzotriazole and 1.2 molar equivalents of dicyclohexylcarbodiimide (DCC). The reaction mixture is stirred at a temperature in the range of about 0° C. to 10° C., preferably about 5° C. for a period of about 2 to 6 hours, preferably about 4 hours, and then for a period of about 12 to 24 hours, preferably about 18 hours, at about room temperature. The resulting solid is filtered and washed with a nonpolar organic solvent, e.g., methylene chloride. The filtrate is combined and evaporated. The residue is dissolved in a nonpolar organic solvent, e.g., methylene chloride, washed, dried, evaporated and purified by flash chromatography to yield the desired blocked mercapto lower-alkyl modified thiopeptide, i.e., a compound of Formula 7.

Preparation of Formula I ##STR23##

To a solution of a blocked mercapto lower-alkyl modified thiopeptide, , i.e., a compound of Formula 7, in a solvent, such a methanol/water (about 7:1 ratio), is added about 1 molar equivalent of a deblocking reagent, such as mercuric acetate. The mixture is stirred at about room temperature for a period of about 30 to 90 minutes, preferably about 60 minutes. H₂ S gas is bubbled through the solution for a period of about 15 minutes, water is added and the resulting precipitate is removed by filtration. The filtrate is extracted with a nonpolar organic solvent, e.g., methylene chloride. The extracts are combined, washed with water, and dried with a drying agent, such as Na2SO₄. The solvent is evaporated and the residue is purified by flash chromatography to yield the desired optionally substituted mercapto thiopeptide, i.e., a compound of Formula I.

REACTION SCHEME B

Reaction Scheme B describes the preparation of compounds of Formula I where R² is hydrogen, n is 0, and R¹, R³, and R⁴ are the same as described in the Summary of the Invention.

Preparation of Formula 9 ##STR24##

An amino acid or modified amino acid, i.e., a compound of Formula 8, is combined with about 3.5 molar equivalents of a halogen salt, such as, NaBr, KBr, NaCl, KCl, NaI, KI, preferably, KBr, and a strong acid, e.g., concentrated H₂ SO₄ (about 0.2 mL/molar equivalent) in water at a temperature in the range of about -10° C. to 0° C., preferably about -4° C. To this solution is added about 1.5 molar equivalents of a nitrosating reagent, such as, NaNO₂ over a period of about 1 hour. After completion of the addition, the reaction mixture is stirred for an additional 1 hour. The solution is extracted with a non-polar organic solvent, e.g., methylene chloride. The organic layer is washed, dried and evaporated to yield the desired halo carboxylic acid, i.e., a compound of Formula 9.

Preparation of Formula 10 ##STR25##

About 2 molar equivalents of a base, such as sodium ethoxide, and 9 molar equivalents of a lower t-alkyl mercaptan, such as, t-butylthiol, are combined in a solvent, such as, ethanol at about room temperature under an inert atmosphere with stirring for about 10 minutes. To this is added a solution of a halo optionally substituted carboxylic acid, i.e., a compound of Formula 9, in a solvent, such as, ethanol. The reaction mixture is stirred for a period of about 2 to 4 hours, preferably about 3 hours at about room temperature. The reaction mixture is poured into water, acidified with a weak acid, such as acetic acid and extracted with a nonpolar organic solvent, e.g., methylene chloride. The organic layer is dried with a drying agent, such as Na₂ SO₄, and evaporated to yield the desired lower-alkyl substituted thiocarboxylic acid, i.e., a compound of Formula 10.

Preparation of Formula 11 ##STR26##

To a solution of a lower-alkyl substituted thiocarboxylic acid in an aprotic solvent, such as THF, at a temperature in the range of about -10° C. to 10° C., preferably about 0° C. is added a reducing agent, such as 1M borane/THF (about 2.5 mL/molar equivalent) in a gradual manner over a period of about 15 minutes with stirring. After completion of the addition, stirring is continued for a period of about 2 to 4 hours, preferably 3 hours. The reaction mixture is quenched by gradual addition of cold water. The mixture is extracted with a nonpolar organic solvent, e.g., methylene chloride, washed with a saturated weak base (such as NaHCO₃), washed with an acid (such as HCl), and dried over a drying agent (such as Na₂ SO₄). The solvent is removed by vacuum and the residue purified by flash chromatography to yield the desired lower-alkyl thioalkylalcohol, i.e., a compound of Formula 11.

Preparation of Formula 12 ##STR27##

About 2 molar equivalents of triphenylphosphine and 2 molar equivalents of a dialkyl azodicarboxylate, such as diisopropyl azodicarboxylate, are combined with an aprotic solvent, such as THF at a temperature in the range of about -10° C. to 10° C., preferably about 0° C. After the ingredients are combined, the solution is stirred for a period of about 15 to 45 minutes, preferably about 30 minutes. The solution yields a precipitate which is combined with a lower-alkyl thioalcohol, i.e., compound of Formula 11. The solution is stirred for about 10 min, and about 2 molar equivalents of thiolacetic acid is added. The reaction mixture is stirred at about 0° C. for 1 hour, and at about room temperature for about 1 hour. The solvent is removed by vacuum, and the residue purified by flash chromatography to yield the desired lower-alkyl thioalkyl acetylthio compound, i.e., a compound of Formula 12.

Preparation of Formula 14 ##STR28##

A lower-alkyl thioalkyl acetylthio compound, i.e., a compound of Formula 12 is combined in a solution with about 2 molar equivalents of a base such as sodium ethoxide in a solvent, such as ethanol, with stirring at about room temperature under an inert atmosphere. To this solution is added about 1 molar equivalent of an α-halo amino acid, or modified amino acid, i.e., a compound of Formula 2 with stirring. After completion of the addition, stirring is continued at about room temperature for a period of about 3 to 5 hours, preferably about 4 hours. The reaction mixture is added to water, acidified with a weak acid (such as, acetic acid) and extracted with a nonpolar organic solvent, e.g., methylene chloride. The organic layer is dried over a drying agent (such as Na₂ SO₄) and evaporated. The residue is purified by chromatography, such as flash chromatography (15% ethyl acetate in hexane) to yield the desired optionally substituted thioalkylcarboxylic acid, i.e., a compound of Formula 14.

Preparation of Formula 15 ##STR29##

An optionally substituted thioalkylcarboxylic acid, is coupled to an optionally modified amino acid, or peptide fragment, i.e., a compound of Formula 6, by following the procedure described previously for the Preparation of Formula 7 (Reaction Scheme A) yielding the desired blocked mercapto peptide, i.e., a compound of Formula 15.

Preparation of Formula 16 ##STR30##

A solution of the blocked mercapto peptide and glacial acetic acid (about 3 mL/mmole) is formed. To this solution is added about 1 molar equivalent of an arylsulfenyl halide, such as 2-nitrophenylsulfenyl chloride. The mixture is stirred at about room temperature for a period of about 1 to 3 hours, preferably about 2 hours. The glacial acetic acid is evaporated under vacuum and the residue purified by chromatography, e.g., flash chromatography (35% ethyl acetate in hexane) to yield the desired aryldisulfide blocked modified peptide, i.e., a compound of Formula 16.

Preparation of Formula I ##STR31##

An aryldisulfide blocked modified peptide is dissolved in a solvent(s), such as a combination of methanol and dioxane (4:1 ratio) to this solution is added 2-mercaptoethanol (about 1.5 mL/molar equivalent) and about 100 molar equivalents of a NaOH solution. The mixture is stirred at about room temperature under an inert atmosphere for a period of about 15 to 45 minutes, preferably about 30 minutes. The reaction mixture is poured into water, acidified with a weak acid, and extracted with a nonpolar organic solvent, e.g., methylene chloride. The organic layer is dried over a drying agent (e.g., Na₂ SO₄) and evaporated under vacuum. The residue is purified by chromatography, such as flash chromatography (25% ethyl acetate in hexane) to yield the desired optionally substituted mercapto peptide, i.e., a compound of Formula I.

REACTION SCHEME C Preparation of Formula 17 ##STR32##

A lower-alkyl thioalkyl acetylthio compound, i.e., a compound of Formula 12A (prepared e.g., according to the procedures described in Reaction Scheme B for the preparation of a compound of Formula 12), is combined with about 1 molar equivalent of Na in an alcohol solvent, such as ethanol, under an inert atmosphere. The mixture is stirred for about 15 min, poured into water, acidified with a weak acid (e.g., acetic acid) and extracted with a nonpolar organic solvent, e.g., methylene chloride. The organic layer is dried over a drying agent (e.g., Na₂ SO4), and evaporated to yield the crude desired lower-alkyl thioalkyl mercaptan, i.e., a compound of Formula 17. The compound is taken to the next step without further purification.

Preparation of Formula 18 ##STR33##

A lower t-alkyl thioalkyl mercaptan is dissolved in a nonpolar solvent, such as, methylene chloride, THF, diethyl ether, preferably methylene chloride, to this solution is added about 1.5 molar equivalents of a base, such as a lower-alkyl amine, preferably ethyl diisopropylamine, and about 1.2 molar equivalents of N-(bromomethyl)phthalimide with stirring at about room temperature under an inert atmosphere. After completion of the addition, the reaction mixture is stirred at about room temperature for a period of about 12 to 24 hours, preferably about 18 hours. The mixture is diluted with a nonpolar solvent, such as, methylene chloride, THF, diethyl ether, preferably methylene chloride, and extracted with 1M HCl. The organic layer is dried over a drying agent, and evaporated under vacuum. The residue is purified by chromatography, e.g., flash chromatography (10% ethyl acetate in hexane) to yield the desired lower t-alkyl thioalkyl phthalimide substituted compound, i.e., a compound of Formula 18.

Preparation of Formula 19 ##STR34##

A lower t-alkyl thioalkyl phthalimide substituted compound is combined with acetic acid (about 2.7 mL/molar equivalent). To this solution is added about 1 molar equivalent of an arylsulfenyl halide, such as 2-nitrobenzenesulfenyl chloride. The reaction mixture is stirred at about room temperature for about 2 hours. The acetic acid is removed by evaporation, and the resulting residue is purified by chromatography, e.g., flash chromatography (10% ethyl acetate in hexane), yielding the desired aryldisulfide phthalimide substituted compound, i.e., a compound of Formula 19.

Preparation of Formula 20 ##STR35##

An aryldisulfide phthalimide substituted compound is dissolved in a solvent or combination of solvents (e.g., methanol/dioxane at about a 2:1 ratio). To this solution is added about 20 molar equivalents of 2-mercaptoethanol and about 1 molar equivalent of NaOH. The reaction mixture is stirred at about room temperature for about 30 minutes under an inert atmosphere. The mixture is poured into water, acidified with a weak acid, and extracted with a nonpolar solvent (e.g., methylene chloride). The organic layer is dried over a drying agent (e.g., Na₂ SO₄) and evaporated. The residue is purified by chromatography, e.g., flash chromatography (35% ethyl acetate in hexane) to yield the desired phthalimide substituted mercaptan compound, i.e., a compound of Formula 20.

Preparation of Formula 22 ##STR36##

A phthalimide substituted mercaptan compound is combined with about 1.1 molar equivalents of an optionally substituted lower t-alkyl ester blocked optionally substituted α-halo amino acid (i.e., a compound of Formula 2, prepared as described in Reaction Scheme A that has been blocked at the --OH) in a solvent, such as acetonitrile. To this solution is added about 2 molar equivalents of N,N-diisopropylethylamine. The reaction mixture is stirred at about room temperature for a period of about 24 to 72 hours, preferably about 48 hours, under an inert atmosphere. The solvent is removed by evaporation, the resulting residue dissolved in a nonpolar organic solvent (e.g., methylene chloride), washed, and extracted with 1M HCl. The organic layer is isolated, dried over a drying agent, and evaporated under vacuum. The residue is purified by chromatography, e.g., flash chromatography (5% ethyl acetate in hexane), to yield the desired blocked C- and N-terminus modified peptide, i.e., a compound of Formula 22.

Preparation of Formula 23 ##STR37##

A blocked C- and N-terminus modified peptide, i.e., a compound of Formula 22, is combined with trifluoroacetic acid (about 1 mL/mmole equivalent) and water (about 38 μL/mmole). The reaction mixture is stirred at about 5° C. for a period of about 12 to 24 hours, preferably about 18 hours. The solvent is removed by vacuum and the residue purified by chromatography, e.g., flash chromatography (45% ethyl acetate in hexane) to yield the desired blocked N-terminus compound, i.e., a compound of Formula 23.

Preparation of Formula 24 ##STR38##

An blocked N-terminus compound is coupled to an optionally modified amino acid, or peptide fragment, i.e., a compound of Formula 6, by following the procedure described previously for the Preparation of Formula 7 (Reaction Scheme A) yielding the desired correspondingly optionally substituted blocked N-terminus peptide, i.e., a compound of Formula 24.

Preparation of Formula 25 ##STR39##

An optionally substituted blocked N-terminus peptide is combined with acetic acid. To this solution is added about 1.1 molar equivalents of an arylsulfenyl halide, such as 2-nitrobenzenesulfenyl chloride. The reaction mixture is stirred at about room temperature for a period in the range of about 12 to 24 hours, preferably about 18 hours. The acetic acid is removed by vacuum, and the residue purified by chromatography, e.g., flash chromatography (5% ethyl acetate in methylene chloride), yielding the desired correspondingly optionally substituted aryldisulfide peptide, i.e., a compound of Formula 25.

Preparation of Formula I ##STR40##

An optionally substituted aryldisulfide peptide is deblocked at the N-terminus by following the procedure described previously for the Preparation of Formula I (Reaction Scheme B) to yield the desired optionally substituted modified mercapto thiopeptide, i.e., a compound of Formula I.

PREFERRED COMPOUNDS

Presently preferred is the compound of Formula I where n is 0.

Especially preferred is the compound of Formula I where R³ is 2 -methylpropyl.

Also especially preferred is the compound of Formula I where R⁴ is phenylmethyl.

Also especially preferred is the compound of Formula I where R⁵ is methyl or benzyl.

Also especially preferred in the compound of Formula I where the carbon to which R³ is attached is in the D-configuration.

Also especially preferred is the compound of Formula I where R¹ and R² are hydrogen.

Also especially preferred is the compound of Formula I where R¹ is methyl, amino(n-butyl), PhtN(n-butyl), 2-aminoethyl, 2-PhtN(ethyl) or carbamoylmethyl.

Also especially preferred is the compound of Formula I where R² is methyl or i-butyl.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is methyl, R¹ and R² are hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is methyl, R¹ is methyl, R² is hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is methyl, R¹ is PhtNBu, R² is hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is methyl, R¹ is PhtNEt, R² is hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is benzyl, R¹ and R² are hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is benzyl, R¹ is methyl, R² is hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is benzyl, R¹ is PhtNBu, R² is hydrogen, and the carbon to which R³ is attached is in the D-configuration.

Of the compound where n is 0, most preferred is the compound of Formula I where R³ is 2-methylpropyl, R⁴ is phenylmethyl, R⁵ is benzyl, R¹ is PhtNEt, R² is hydrogen, and the carbon to which R³ is attached is in the D-configuration.

UTILITY, TESTING AND ADMINISTRATION General Utility

The compounds of this invention, including the pharmaceutically acceptable esters, ethers, or salts thereof, and the compositions containing them are useful for modulating physiological functions or treating diseases and disease conditions associated with the modulation of MMP activity, e.g., arthritic diseases, such as osteoarthritis (OA), rheumatoid arthritis (RA), septic arthritis, soft tissue rheumatism, polychondritis and tendonitis; tumor invasion in certain cancers, periodontal diseases; corneal ulceration, e.g., that induced by alkali or other burns, by radiation, by vitamin E or retinoid deficiency; glomerular diseases, such as proteinuria, dytrophobic epidermolysis bullosa; bone resorption diseases, such as osteoporosis, Paget's disease, hyperparathyroidism and cholesteatoma; birth control through preventing ovulation or implantation; angiogenesis relating to tumor growth on to the neovascularization associated with diabetic retinopathy and macular degeneration; coronary thrombosis associated with atherosclerotic plaque rupture; and pulmonary emphysema.

The compounds of this invention inhibit MMP, thereby providing a means of controlling conditions (normal physiological or disease states) modulated or mediated by MMP, particularly those where elevated levels of MMP have been detected.

All forms of arthritis (i.e., arthritic diseases soft tissue rheumatism, polychondritis and tendonitis) are characterized by the erosion of the articular cartilage of affected joints. Since cartilage consists primarily of proteoglycans and type II collagen, proteinases capable of attacking both macromolecules have been implicated in the progression of the diseases [Harris et al., (1969) Arthritis Rheum. 12, 92-102; Harris et al., (1970) Arthritis Rheum. 13, 83-95; Woolley et al., (1977) Arthritis Rheum. 20, 1231-1239; and Krane, S. M., (1981) Ann. Rheum. Dis. 40, 433-448].

The metastasis of tumor cells is a process that is inhibited by the connective tissue barriers of the host. The association of both interstitial collagenases and proteinases capable of degrading type IV collagen found in basement membrane is well documented and is believed to facilitate metastasis [Strauli et al., (1980) Proteinases and Tumor Invasion, Raven Press, New York; Liotta et al., (1991) Tumor Invasion and Metastasis, pp. 319-333, Martinus Nijhoff, Dordrecht; Blood, C. H. and Zetter, B. R., (1990) Biochim. Biophys. Acta 1032, 89-118; Liotta et al., (1983) Lab. Invest. 49, 636-649; and Liotta et al., (1980) Nature (London) 284, 67-68].

Periodontal disease is an inflammatory disease that is triggered by bacteria that inhabit the gingival cavity. Periodontis is characterized by the progressive loss of the attachment apparatus of teeth. Since the major protein component of gingival tissue and bone is type I collagen, collagenases are believed to participate in the progression of the disease [Robertson, P. B. and simpson, J. (1976) J. Periodontol., 47, 29-33; and Birkedal-Hansen, H., (1980) in Collagenases in Normal and Pathological Connective Tissue, (Woolley, D. E. and Evanson, J. M., eds), pp. 127-140, Wiley and Sons, New York].

Corneal ulceration can be brought about by chemical or thermal burns, infections Stevens-Johnson syndrome, Mooren's ulcer, vitamin A deficiency, and many other diseases. The corneal stroma is composed predominantly of type I collagen that is progressively degraded during ulceration [Van Wart, H. E. and Mookhtiar, K. A. (1990) in Biological Response Modifiers for Tissue Repair (Grotendorst, G., Jhelmeland, L. M. and Gills, J. P., eds), pp. 23-50, Portfolio, The Woodlands, Tex.; Brown et al., (1969) Arch. Ophthalmol. 81, 370-373; and Berman, M. B. (1980) in Collagenases in Normal and Pathological Connective Tissue, (Woolley, D. E. and Evanson, J. M., eds), pp. 141-174, Wiley and Sons, New York].

Glomerular diseases, such as proteinuria, dytrophobic epidermolysis bullosa, which a separation of the dermis and epidermis, are believed to be influenced by collagenases [Eisen, A. Z. (1969) J. Invest. Dermatol. 52, 449-453].

Bone resorption diseases, such as osteoporosis, Paget's disease, hyperparathyroidism and cholesteatoma, are believed to involve the action of collagenases [Vaes, G. (1980) in Collagenases in Normal and Pathological Connective Tissue, (Woolley, D. E. and Evanson, J. M., eds), pp. 185-207, Wiley and Sons, New York; Gardner et al., (1971) Surg. Forum, 22, 435-437; Abramson, M. (1969) Ann. Otol. Rhinol. Laryngol., 78, 112-124; Sakamoto et al., (1975) Biochem. Biophys. Res. Commun. 63, 172-177; Griffith et al., (1965) J. Am. Med. Assoc. 193, 91-94; and Eeckhout et al., (1986) Biochem. J. 239 793-796].

Certain MMP have been reported as mediating ovulation and implantation, thus inhibition of these MMP would provide a means of birth control [Librach et al., J. Cell Biol., 13, 437-449, 1991; and Brannstrom et al., Endocrinology, 122, 5, 1715-1721, 1988].

Certain MMP have been associated with angiogenesis relating to tumor growth or to the neovascularization associated with diabetic retinopathy and macular degeneration. Inhibition of these MMP would provide a means of slowing or halting the development of such conditions [Moses et al., Bio/technology, 9, 630-634, 1991; and Langer et al., Proc. Natl. Aca. Sci. USA, 77, 7, 4331-4335, 1980)].

MMP have been linked with coronary thrombosis caused by atherosclerotic plaque rupture [Henney et al., Proc. Natl. Acad. Sci., 88, 8154-8158, 1991]. Inhibition of MMP could alleviate this condition.

Interstitial collagenase has been implicated as a possible etiological agent in the emphysema disease process. Although elastase has been proposed as the primary enzyme responsible for emphysematous lung damage, there is evidence that other extra-ceullular matrix proteases could play a role in emphysema [D'Armiento et al., Cell, 71, 955-961 Dec. 11, 1992].

Testing

The potency and selectivity of compounds of the present invention as inhibitors of MMP are determined by assay against MMPs that are associated with the metabolic turnover of interstitial collagens in the extracellular matrix of humans. For example, following the procedures described in Example 21, or modifications thereof.

Five types of MMP are assayed, i.e., fibroblast-type collagenase (HFC), gelatinase (HFG) and stromelysin (HFS) and neutrophil-type collagenase (HNC) and gelatinase (HNG).

The assay method is based on the hydrolysis of DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg as the substrate (according to Netzel-Arnett, S.; Mallya, S. K.; Nagase, H.; Birkedal-Hansen, H.; Van Wart, H. E. Anal. Biochem. 1991, 195, 86-92).

Administration

The compounds of this invention are administered at a therapeutically effective dosage, i.e., that amount which, when administered to a mammal in need thereof, is sufficient to effect treatment, as described above (for example, to reduce or otherwise treat inflammation, pain and/or pyrexia in the mammal). Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for agents that serve similar utilities.

The level of the drug in a formulation can vary within the full range employed by those skilled in the art, e.g., from about 0.01 percent weight (% w) to about 99.99% w of the drug based on the total formulation and about 0.01% w to 99.99% w excipient. Preferably the drug is present at a level of about 10% w to about 70% w.

Generally, an acceptable daily dose is of about 0.001 to 50 mg per kilogram body weight of the recipient per day, preferably about 0.05 to 25 mg per kilogram body weight per day, and most preferably about 0.01 to 10 mg per kilogram body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 0.07 mg to 3.5 g per day, preferably about 3.5mg to 1.75 g per day, and most preferably about 0.7 mg to 0.7 g per day depending upon the individuals and disease state being treated. Such use optimization is well within the ambit of those of ordinary skill in the art.

Administration can be via any accepted systemic or local route, for example, via parenteral, oral (particularly for infant formulations), intravenous, nasal, bronchial inhalation (i.e., aerosol formulation), transdermal or topical routes, in the form of solid, semi-solid or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, aerosols, emulsions or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and an active compound of Formula I and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Carriers can be selected from the various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Other suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

The compounds of this invention are generally administered as a pharmaceutical composition which comprises a pharmaceutical excipient in combination with a compound of Formula I. The level of the drug in a formulation can vary within the full range employed by those skilled in the art, e.g., from about 0.01 percent weight (% w) to about 99.99% w of the drug based on the total formulation and about 0.01% w to 99.99% w excipient. Preferably, the formulation will be about 3.5 to 60% by weight of the pharmaceutically active compound, with the rest being suitable pharmaceutical excipients.

Intravenous Administration

Intravenous injection has proven to be an important route of administration for therapeutic agents. The compounds of the present invention can be administered via this route, for example, by dissolving the compound, ester, ether or salt in a suitable solvent (such as water or saline) or incorporation in a liposomal formulation followed, by dispersal into an acceptable infusion fluid. A typical daily dose of a compound of the invention can be administered by one infusion, or by a series of infusions spaced over periodic intervals.

Oral Administration

Oral administration can be used to deliver the compound of Formula I using a convenient daily dosage regimen which can be adjusted according to the degree of affliction or for renal impairment, or to compensate for the toxic effects of other medications administered contemporaneously. For such oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain between 0.01 wt/wt % and 99.99 wt/wt % of the compound of Formula I, but preferably such compositions will contain between 25 wt/wt % and about 80 wt/wt %.

Preferably the compositions will take the form of a capsule, pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalciumphosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, polyvinylpyrrolidone, gum acacia, gelatin, cellulose and derivatives thereof, and the like. For oral administration to infants, a liquid formulation (such as a syrup or suspension) is preferred.

Liposomal Formulations

Pharmaceutical formulations based on liposomes have recently reached human clinical trials. Their benefits are believed related to favorable changes in tissue distribution and pharmacokinetic parameters that result from liposome entrapment of drugs, and may be applied to the compounds of the present invention by those skilled in the art.

The formulations can be designed to either target drug to disease sites [see: Lopez-Berestein et al., J. Infect. Dis., 151:704-710 (1985); Gotfredsen et al., Biochemical Pharmacology, 32:3389-3396 (1983)]; or to the reticuloendothelial system [see Eppstein et al., Int. J. Immunotherapy, 2: 115-126 (1986)], to increase duration of drug action [see: Gabizon et al., Cancer Res., 42:4734 (1982); Eppstein et al., Delivery Systems for Peptide Drugs, Eds. S. S. Davis, L. Illum and E. Tomlinson, Plenum Pub. Corp., New York, pp. 277-283; C. A. Hunt, Biochemica et Biophysica Acta., 719:450-463 (1982); and Senior et al., Biochemica et Biophysica Acta., 839:1-8 (1985)], or to divert a drug away from organs that are particularly sensitive to its toxic effects [see: Weinstein et al., Pharmac. Ther., 24:207-233 (1983); Olson et al., Eur. J. Cancer Clin. Oncol., 18:167-176 (1982); and Gabzion et al., supra.] .

Controlled release liposomal liquid pharmaceutical formulations for injection or oral administration are described in U.S. Pat. No. 4,016,100. Liposomal applications for oral drug delivery of a lyophilized liposome/peptide drug mixture filled into intestine capsules have also been suggested, see U.S. Pat. No. 4,348,384. The foregoing are incorporated herein by reference.

Suppositories

For systemic administration via suppository, traditional binders and carriers include, for example, polyalkaline glycol or triglycerides [e.g., PEG 1000 (96%) and PEG 4000 (4%)]. Such suppositories may be formed from mixtures containing active ingredients in the range of from about 0.5 wt/wt % to about 10 wt/wt %; preferably from about 1 wt/wt % to about 2 wt/wt %.

Liquids

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound (about 0.5% to about 20%), as described above, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Ed., 1980. The composition to be administered will, in any event, contain a quantity of the active compound(s) in a pharmaceutically effective amount for relief of the particular condition being treated in accordance with the teachings of this invention.

EXAMPLES

The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

EXAMPLE 1 Preparation of (2R) 2-Bromo-4-Methylpentanoic Acid

1A. Formula 2 Where X Is Bromo and R³ Is 2-Methylpropyl

A solution of 3.00 g of D-Leu, 9.53 g of KBr in 15 mL of water and 4.5 mL of conc. H₂ SO₄ was formed and stirred at -4° C. To this solution was added 2.09 g of NaNO₂ in 10 mL of water over a period of 1 h. Stirring was continued for 1 h at the same temperature, then the reaction mixture was extracted with CH₂ Cl₂. The organic layer was washed with water, dried over Na₂ SO₄ and evaporated under vacuum to give 3.72 g of (2R)-2-bromo-4-methylpentanoic acid at 83% yield as a colorless oil. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) d 4.31 (t, J=8 Hz, 1H), 1.94 (t, J=7 Hz, 2H), 1.82 (m, 1H), 0.98 (d, J=7 Hz, 3 H), 0.93 (d, J=7 Hz, 3H); [α]_(D) ²⁵ +39.0° (c=2.02, MeOH).

1B. Preparation of the Corresponding (2S) Isomer of Formula 2

By following the same procedures described in Example 1A and substituting L-Leu for D-Leu, (2S)-2-bromo-5-methylpentanoic acid was obtained in 83% yield. Characteristic analytical data are as follows: [α]_(D) ²⁵ -39.8° (c=2.00, MeOH); [α]₅₄₆ ²⁵ -47.5° (c=2.00, MeOH).

1C. Formula 2 Varying R³

By following the procedures described in Example 1A and substituting D-Leu with other compounds of Formula 1 and KBr with other halo salts there are obtained the correspondingly substituted compounds of Formula 2 (where R³ is as indicated in the table below).

    ______________________________________                                         Formula 2                                                                       ##STR41##                                                                     X   R.sup.3       Name                                                         ______________________________________                                         Cl  hydrogen      2-chloroethanoic acid                                        Br  methyl        (2R)-2-bromopropanoic acid                                   Br  2-propyl      (2R)-2-bromo-3-methylbutanoic acid                           Cl  2-butyl       (2R)-2-chloro-3-methylpentanoic acid                         Br  benzyl        (2R)-2-bromo-3-phenylpropanoic acid                          Br  blocked 4-hydroxy-                                                                           (2R)-2-bromo-3-(4-hydroxyphenyl)                                 phenylmethyl  propanoic acid                                               Br  blocked 3-indolyl-                                                                           (2R)-2-bromo-3-(3-indolyl)propanoic                              methyl        acid                                                         Br  4-methoxyphenyl-                                                                             (2R)-2-bromo-3-(4-methoxyphenyl)                                 methyl        propanoic acid                                               Cl  phenylethyl   (2R)-2-chloro-4-phenylbutanoic acid                          ______________________________________                                    

1D. Formula 2 Varying R³

By following the procedures described in Example 1A and substituting L-Leu with other compounds of Formula 1 and KBr with other halo salts there are obtained the correspondingly substituted compounds of Formula 2 (where R³ is as indicated in the table below).

    ______________________________________                                         Formula 2                                                                       ##STR42##                                                                     X   R.sup.3       Name                                                         ______________________________________                                         Br  methyl        (2S)-2-bromopropanoic acid                                   Br  2-propyl      (2S)-2-bromo-3-methylbutanoic acid                           Cl  2-butyl       (2S)-2-chloro-3-methylpentanoic acid                         Br  benzyl        (2S)-2-bromo-3-phenylpropanoic acid                          Br  blocked 4-hydroxy-                                                                           (2S)-2-bromo-3-(4-hydroxyphenyl)                                 phenylmethyl  propanoic acid                                               Br  blocked 3-indolyl-                                                                           (2S)-2-bromo-3-(3-indolyl)propanoic                              methyl        acid                                                         Br  4-methoxyphenyl-                                                                             (2S)-2-bromo-3-(4-methoxyphenyl)                                 methyl        propanoic acid                                               Cl  phenylethyl   (2S)-2-chloro-4-phenylbutanoic acid                          ______________________________________                                    

EXAMPLE 2 Preparation of HS(CH₂)₂ --(S-D-Leu)-Oh

2A. Formula 4 Where n is 0, R¹ and R² Are Hydrogen and R³ is 2-Methylpropyl

To a solution of 2.4 g of Na in 50 mL of EtOH was added 50 mL of ethanedithiol with stirring at room temperature under nitrogen. After 10 min a solution of 8.1 g of (2S)-2-bromo-4-methylpentanoic acid in 10 mL of EtOH was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into water and was acidified with acetic acid and extracted with CH₂ C12. The organic layer was dried over Na₂ SO₄ and the solvent and excess ethanedithiol were evaporated under vacuum. Purification of the residue by flash chromatography (15% EtOAc in hexane) afforded 4.63 g of HS(CH₂)₂ --(S-D-Leu)-OH as a colorless gum at 54% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) d 3.34 (t, J=7 Hz, 1H), 2.70-3.02 (m, 4H), 1.78 (m, 2H), 1.70 (t, J=8 Hz, 1H, SH), 1.55 (m, 1H), 0.94 (d, J=6 Hz, 3H), 0.93 (d, J=6 Hz, 3H); [α]_(D) ²⁵ +76.2° (c=2.04, MeOH).

2B. Preparation of the Corresponding (S-L-Leu) Isomer of Formula 4

By following the procedure described in Example 2A and substituting (2S)-2-bromo-4-methylpentanoic acid with (2R)-2-bromo-4-methylpentanoic acid, HS(CH₂)₂ --(S-L-Leu)-OH was obtained at 57% yield. Characteristic analytical data are as follows: [α]_(D) ²⁵ -71.8° (c=1.78, MeOH).

2C. Formula 4 Varying R³

By following the procedures described in Example 2A and substituting (2S)-2-bromo-4-methylpentanoic acid with other compounds of Formula 2 there are obtained the correspondingly substituted of compounds of Formula 4 (where R³ is as indicated in the table below).

    __________________________________________________________________________     Formula 4                                                                       ##STR43##                                                                     R.sup.3         Name                                                           __________________________________________________________________________     hydrogen        HS(CH.sub.2).sub.2 (SGly)OH                                    methyl          HS(CH.sub.2).sub.2 (SDAla)OH                                   2-propyl        HS(CH.sub.2).sub.2 (SDVal)OH                                   2-butyl         HS(CH.sub.2).sub.2 (SDIle)OH                                   benzyl          HS(CH.sub.2).sub.2 (SDPhe)OH                                   blocked 4-hydroxyphenylmethyl                                                                  HS(CH.sub.2).sub.2 (SDTyr)OH                                   blocked 3-indolylmethyl                                                                        HS(CH.sub.2).sub.2 (SDTrp)OH                                   4-methoxyphenylmethyl                                                                          HS(CH.sub.2).sub.2 (SDTyrOCH.sub.3)OH                          phenylethyl     HS(CH.sub.2).sub.2 (SDPhet)OH                                  __________________________________________________________________________

2D. Formula 4 Varying R³

By following the procedures described in Example 2B and substituting (2R)-2-bromo-4-methylpentanoic acid with other compounds of Formula 2 there are obtained the correspondingly substituted of compounds of Formula 4 (where R³ is as indicated in the table below).

    __________________________________________________________________________     Formula 4                                                                       ##STR44##                                                                     R.sup.3         Name                                                           __________________________________________________________________________     methyl          HS(CH.sub.2).sub.2 (SLAla)OH                                   2-propyl        HS(CH.sub.2).sub.2 (SLVal)OH                                   2-butyl         HS(CH.sub.2).sub.2 (SLIle)OH                                   benzyl          HS(CH.sub.2).sub.2 (SLPhe)OH                                   blocked 4-hydroxyphenylmethyl                                                                  HS(CH.sub.2).sub.2 (SLTyr)OH                                   blocked 3-indolylmethyl                                                                        HS(CH.sub.2).sub.2 (SLTrp)OH                                   4-methoxyphenylmethyl                                                                          HS(CH.sub.2).sub.2 (SLTyrOCH.sub.3)OH                          phenylethyl     HS(CH.sub.2).sub.2 (SLPhet)OH                                  __________________________________________________________________________

2E. Formula 4 Varying n, R¹, R² and R³

By following the procedures described in Example 2A and substituting ethanedithiol with other compounds of Formula 3 and (2S)-2-bromo-4-methylpentanoic acid with other compounds of Formula 2 (e.g., compounds with R³ that are prepared according to Example 1A) there are obtained the correspondingly substituted compounds of Formula 4 (where n, R¹, R² and R³ are as indicated in the table below).

    ______________________________________                                         Formula 4                                                                       ##STR45##                                                                     n   R.sup.1     R.sup.2     R.sup.3                                            ______________________________________                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-methylpropyl                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 4-hydroxy-                                                             phenylmethyl                                           0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 3-indolyl-                                                             methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            0   methyl      methyl      hydrogen                                           0   n-butyl     n-butyl     methyl                                             0   benzyl      benzyl      2-propyl                                           0   phenylethyl phenylethyl 2-butyl                                            0   blocked     blocked     benzyl                                                 aminomethyl aminomethyl                                                    0   methyl-     methyl-     blocked 4-hydroxy-                                     carbonylethyl                                                                              carbonylethyl                                                                              phenylmethyl                                       0   PhtN-methyl PhtN-methyl blocked 3-indolyl-                                                             methyl                                             0   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              0   TsNH-methyl TsNH-methyl phenylethyl                                        1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         benzyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 4-hydroxy-                                                             phenylmethyl                                           1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 3-indolyl-                                                             methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            1   methyl      methyl      hydrogen                                           1   n-butyl     n-butyl     methyl                                             1   benzyl      benzyl      2-propyl                                           1   phenylethyl phenylethyl 2-butyl                                            1   blocked     blocked     benzyl                                                 aminomethyl aminomethyl                                                    1   methyl-     methyl-     blocked 4-hydroxy-                                     carbonylethyl                                                                              carbonylethyl                                                                              phenylmethyl                                       1   PhtN-methyl PhtN-methyl blocked 3-indolyl-                                                             methyl                                             1   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              1   TsNH-methyl TsNH-methyl phenylethyl                                        ______________________________________                                    

EXAMPLE 3 Preparation of BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-OH

3A. Formula 5 Where n Is 0, R¹ and R² Are Hydrogen and R³ Is 2-Methylpropyl

To a mixture of 4.63 g of HS (CH₂)₂ - (S-D-Leu)--OH and 3.53 g of BzNHCH₂₀ H was added 50 mL of trifluoroacetic acid with stirring at 0° C. After completion of the addition, the reaction mixture was stirred for an additional hour. The trifluoroacetic acid was evaporated under vacuum and the residue was passed through silica gel (25% EtOAc in hexane) to give 7.21 g of BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-OH as a colorless gum 95% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ7.81 (d, J=8 Hz, 2H), 7.54 (t, J=8 Hz, 1H), 7.45 (t, J=8 Hz, 2H), 6.83 (br t, J=6 Hz, 1H, NH), 4.63 (dd, J=6, 14 Hz, 1H), 4.58 (dd, J=6, 14 Hz, 1H), 3.42 (dd, J=7, 9 Hz, H), 2.73-3.04 (m, 4H), 1.74 (m, 2H), 1.50 (m, 1H), 0.91 (d, J=6 Hz, 3H), 0.89 (d, J=6 Hz, 3H).

3B. Preparation of the Corresponding (S-L-Leu) Isomer of Formula 5

By following the procedure in Example 3A and substituting HS (CH₂)₂ --(S-L-Leu)--OH for HS(CH₂)₂ --(S-D-Leu)-OH, BzNHCH₂ S(CH₂)₂ --(S-L-Leu)-OH was obtained as a colorless gum at 92% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ7.79 (d, J=7 Hz, 2H), 7.53 (t, J=7 Hz, 1H), 7.43 (t, J=7 Hz, 2H), 7.06 (br s, 1H, NH), 4.68 (dd, J=7, 14 Hz, 1H), 4.54 (dd, J=6, 14 Hz, 1H), 3.40 (dd, J=7, 9 Hz, 1H), 2.73-3.05 (m, 4H), 1.65-1.82 (m, 2H), 1.50 (m, 1H), 0.90 (d, J=6 Hz, 3H), 0.88 (d, J=6 Hz, 3H).

3C. Formula 5 Varying R³

By following the procedures described in Example 3A and substituting HS(CH₂)₂ --(S-D-Leu)-OH with other compounds of Formula 4 (e.g., compounds that are prepared according to Examples 2A) there are obtained the correspondingly substituted of compounds of Formula 5 (where n, R¹, R² and R³ are as indicated in the table below).

    __________________________________________________________________________     Formula 5                                                                       ##STR46##                                                                     R.sup.3         Name                                                           __________________________________________________________________________     hydrogen        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SGly)OH                        methyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDAla)OH                       2-propyl        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDVal)OH                       2-butyl         BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDIle)OH                       benzyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDPhe)OH                       blocked 4-hydroxyphenylmethyl                                                                  BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDTyr)OH                       blocked 3-indolylmethyl                                                                        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDTrp)OH                       4-methoxyphenylmethyl                                                                          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDTyrOCH.sub.3)OH              phenylethyl     BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDPhet)OH                      __________________________________________________________________________

3D. Formula 5 Varying R³

By following the procedures described in Example 3B and substituting HS(CH₂)₂ --(S-L-Leu)-OH with other compounds of Formula 4 (e.g., compounds that are prepared according to Examples 2B) there are obtained the correspondingly substituted of compounds of Formula 5 (where n, R¹, R² and R³ are as indicated in the table below).

    __________________________________________________________________________     Formula 5                                                                       ##STR47##                                                                     R.sup.3         Name                                                           __________________________________________________________________________     methyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLAla)OH                       2-propyl        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLVal)OH                       2-butyl         BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLIle)OH                       benzyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLPhe)OH                       blocked 4-hydroxyphenylmethyl                                                                  BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLTyr)OH                       blocked 3-indolylmethyl                                                                        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLTrp)OH                       4-methoxyphenylmethyl                                                                          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLTyrOCH.sub.3)OH              phenylethyl     BzNHCH.sub.2 S(CH.sub.2).sub.2 (SLPhet)OH                      __________________________________________________________________________

3E. Formula 5 Varying n, R¹, R² and R³

By following the procedures described in Example 3A and substituting HS(CH₂)₂ --(S-D-Leu)-OH with other compounds of Formula 4 (e.g., compounds that are prepared according to Examples 2A-2E) there are obtained the correspondingly substituted of compounds of Formula 5 (where n, R¹, R² and R³ are as indicated in the table below).

    ______________________________________                                         Formula 5                                                                       ##STR48##                                                                     n   R.sup.1     R.sup.2     R.sup.3                                            ______________________________________                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-methylpropyl                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 4-hydroxy-                                                             phenylmethyl                                           0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 3-indolyl-                                                             methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            0   methyl      methyl      hydrogen                                           0   n-butyl     n-butyl     methyl                                             0   benzyl      benzyl      2-propyl                                           0   phenylethyl phenylethyl 2-butyl                                            0   blocked     blocked     benzyl                                                 aminomethyl aminomethyl                                                    0   methyl-     methyl-     blocked 4-hydroxy-                                     carbonylethyl                                                                              carbonylethyl                                                                              phenylmethyl                                       0   PhtN-methyl PhtN-methyl blocked 3-indolyl-                                                             methyl                                             0   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              0   TsNH-methyl TsNH-methyl phenylethyl                                        1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         benzyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 4-hydroxy-                                                             phenylmethyl                                           1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 3-indolyl-                                                             methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            1   methyl      methyl      hydrogen                                           1   n-butyl     n-butyl     methyl                                             1   benzyl      benzyl      2-propyl                                           1   phenylethyl phenylethyl 2-butyl                                            1   blocked     blocked     benzyl                                                 aminomethyl aminomethyl                                                    1   methyl-     methyl-     blocked 4-hydroxy-                                     carbonylethyl                                                                              carbonylethyl                                                                              phenylmethyl                                       1   PhtN-methyl PhtN-methyl blocked 3-indolyl-                                                             methyl                                             1   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              1   TsNH-methyl TsNH-methyl phenylethyl                                        ______________________________________                                    

EXAMPLE 4 Preparation of BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-Phe-NHMe

4A. Formula 7 Where n Is 0, R¹ and R² Are Hydrogen, R³ Is 2-Methylpropyl, R⁴ Is Benzyl and R⁶ Is Methyl

To a solution of 7.21 g of BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-OH and 3.96 g of PheNHMe in 270 mL of 1,2-dimethoxyethane stirred at 5° C. was added 3.6 g of 1-hydroxybenzotriazole and 5.50 g of dicyclohexylcarbodiimide. The reaction mixture was stirred at 5° C. for 4 h, then at room temperature overnight. The resulting solid was filtered and washed with CH₂ Cl₂. The filtrate was combined and evaporated under vacuum. The residue was dissolved in CH₂ Cl₂ and washed with sat. NaHCO₃, 1N HCl, and water. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum. The residue was purified by flash chromatography (5% EtOAc in CH₂ Cl₂) to give 8.24 g of BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-Phe-NHMe at 78% yield. Characteristic analytical data are as follows: mp 74°-76° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.99 (d, J=8 Hz, 1H), 7.85 (d, J=7 Hz, 2H), 7.55 (t, J=7 Hz, 1H), 7.46 (t, J=7 Hz, 2H), 7.18-7.31 (m, 6H), 6.28 (m, 1H), 5.03 (dd, J=9, 14 Hz, 1H), 4.68 (dr, J=7, 9 Hz, 1H), 4.28 (dd, J=5, 14 Hz, 1H), 3.37 (dd, J=6, 9 Hz, 1H), 3.14 (dd, J=7, 14 Hz, 1H), 3.00 (dd, J=9, 14 Hz, 1H), 2.82 (m, 2H), 2.74 (d, J=5 Hz, 3H), 2.63 (m, 2H), 1.68 (m, 1H), 1.34 (m, 2H), 0.78 (d, J=7 Hz, 3H), 0.77 (d, J=7 Hz, 3H).

4B. Preparation of the Corresponding (S-L-Leu) Isomer of Formula 7

Using the procedure described for the D-isomer, BzNHCH₂ S(CH₂)₂ --(S-L-Leu)-OH was coupled to PheNHMe to give a 42% yield of BzNHCH₂ S (CH₂)₂ --(S-L-Leu)-Phe-NHMe as a solid: mp 78°-80° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.90 (d, J=7 Hz, 2H), 7.70 (br s, 1H, NH), 7.59 (br s, 1H, NH), 7.53 (t, J=7 Hz, 1H), 7.45 (t, J=7 Hz, 2H), 7.18-7.33 (m, 5H), 6.14 (br s, 1H, NH), 4.69 (dd, J=7, 14 Hz, 1H), 4.63 (br t, J=8 Hz, 1H), 4.29 (dd, J=5, 14 Hz, 1H), 3.31 (t, J=7 Hz, 1H), 3.16 (dd, J=7, 14 Hz, 1H), 3.05 (dd, J= 8, 14 Hz, 1H), 2.53-2.84 (m, 4H), 2.68 (d, J=5 Hz, 3H), 1.58 (m, 2H), 1.36 (m, 1H), 0.83 (d, J=6 Hz, 3H), 0.79 (d, J=6 Hz, 3H).

4C. Formula 7 Varying R⁵

By following the procedures described in Example 4A and substituting BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-OH with other compounds of Formula 5 (where the R³ substituents are as indicated in the table below) there are obtained the correspondingly substituted of compounds of Formula 7.

    __________________________________________________________________________     Formula 7                                                                       ##STR49##                                                                     where R.sup.4 is phenylmethyl, R.sup.5 is CH(R.sup.6) C(O)NH.sub.2             and R.sup.6 is methyl                                                          R.sup.3         Name                                                           __________________________________________________________________________     hydrogen        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SGly)PheNHMe                   methyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDAla)PheNHMe                  2-propyl        BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDVal)PheNHMe                  2-butyl         BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDIle)PheNHMe                  benzyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDPhe)PheNHMe                  blocked 4-hydroxyphenylmethyl                                                                  BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDTyr)PheNHMe                  blocked 3-indolylmethyl                                                                        BzNHCH.sub.2 S(CH.sub.2).sub. 2 (SDTrp)PheNHMe                 4-methoxyphenylmethyl                                                                          BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDTyrOCH.sub.3)PheNHMe         phenylethyl     BzNHCH.sub.2 S(CH.sub.2).sub.2 (SDPhet)PheNHMe                 __________________________________________________________________________

4D. Formula 7 Varying R³

By following the procedures described in Example 4B and substituting BzNHCH₂ S(CH₂)₂ --(S-L-Leu)-OH with other compounds of Formula 5 (where the R³ substituents are as indicated in the table below) there are obtained the correspondingly substituted of compounds of Formula 7.

    __________________________________________________________________________     Formula 7                                                                       ##STR50##                                                                     where R.sup.4 is phenylmethyl, R.sup.5 is CH(R.sup.6)C(O)NH.sub.2              and R.sup.6 is methyl                                                          R.sup.3         Name                                                           __________________________________________________________________________     methyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Ala)PheNHMe                2-propyl        BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Val)PheNHMe                2-butyl         BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Ile)PheNHMe                benzyl          BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Phe)PheNHMe                blocked 4-hydroxyphenylmethyl                                                                  BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Tyr)PheNHMe                blocked 3-indolylmethyl                                                                        BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Trp)PheNHMe                4-methoxyphenylmethyl                                                                          BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-TyrOCH.sub.3)PheNHMe       phenylethyl     BzNHCH.sub.2 S(CH.sub.2).sub.2 (S-L-Phet)PheNHMe               __________________________________________________________________________

4E. Formula 7 Varying n, R¹, R² and R³

By following the procedures described in Example 4A and substituting BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-OH with other compounds of Formula 5 (e.g., compounds that are prepared according to Examples 3A-3F) there are obtained the correspondingly substituted of compounds of Formula 7 (where n, R¹, R² and R³ are as indicated in the table below).

    ______________________________________                                         Formula 7                                                                       ##STR51##                                                                     where R.sup.4 is phenylmethyl, R.sup.5 is CH(R.sup.6)C(O)NH.sub.2              and R.sup.6 is methyl                                                          n   R.sup.1     R.sup.2     R.sup.3                                            ______________________________________                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-methylpropyl                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 4-hydroxy-                                                             phenylmethyl                                           0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 3-indolyl-                                                             methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            0   methyl      methyl      hydrogen                                           0   n-butyl     n-butyl     methyl                                             0   benzyl      benzyl      2-propyl                                           0   phenylethyl phenylethyl 2-butyl                                            0   blocked     blocked     benzyl                                                 aminomethyl aminomethyl                                                    0   methyl-     methyl-     blocked 4-hydroxy-                                     carbonylethyl                                                                              carbonylethyl                                                                              phenylmethyl                                       0   PhtN-methyl PhtN-methyl blocked 3-indolyl-                                                             methyl                                             0   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              0   TsNH-methyl TsNH-methyl phenylethyl                                        1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         benzyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 4-hydroxy-                                                             phenylmethyl                                           1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         blocked 3-indolyl-                                                             methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            1   methyl      methyl      hydrogen                                           1   n-butyl     n-butyl     methyl                                             1   benzyl      benzyl      2-propyl                                           1   phenylethyl phenylethyl 2-butyl                                            1   blocked     blocked     benzyl                                                 aminomethyl aminomethyl                                                    1   methyl-     methyl-     blocked 4-hydroxy-                                     carbonylethyl                                                                              carbonylethyl                                                                              phenylmethyl                                       1   PhtN-methyl PhtN-methyl blocked 3-indolyl-                                                             methyl                                             1   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              1   TsNH-methyl TsNH-methyl phenylethyl                                        ______________________________________                                    

4F. Formula 7 Varying n, R¹, R², R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 4A and substituting BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-OH with other compounds of Formula 5 (e.g., compounds that are prepared according to Examples 3A-3F) and Phe-NHMe with other compounds of Formula 6 there are obtained the correspondingly substituted of compounds of Formula 7 (where n, R¹, R², R³, R⁴, R⁵ and R⁶ are as i the tables below).

    ______________________________________                                         Formula 7                                                                       ##STR52##                                                                     where R.sup.5 is methyl or benzyl                                              n   R.sup.1   R.sup.2   R.sup.3  R.sup.4 R.sup.5                               ______________________________________                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     hydrogen   phenylethyl                                                                            CH.sub.3                                0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     methyl     4-methoxy-                                                                             Bn                                                                     phenyl-                                                                        methyl                                          0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-propyl   blocked 3-                                                                             CH.sub.3                                                               indolyl-                                                                       methyl                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-butyl    blocked 4-                                                                             Bn                                                                     hydroxy-                                                                       phenyl-                                                                        methyl                                          0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-methyl-  benzyl  CH.sub.3                                                    propyl                                                     0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     blocked    blocked 4-                                                                             Bn                                                          4-hydroxy- imidazoyl-                                                          phenylmethyl                                                                              methyl                                          0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     blocked 3- blocked 3-                                                                             CH.sub.3                                                    indolylmethyl                                                                             guanyl-                                                                        propyl                                          0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     4-methoxy- blocked 4-                                                                             Bn                                                          phenylmethyl                                                                              aminobutyl                                      0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     phenylethyl                                                                               2-methyl-                                                                              CH.sub.3                                                    propyl                                                     0   methyl    methyl    hydrogen 2-butyl Bn                                    0   n-butyl   n-butyl   methyl   2-propyl                                                                               CH.sub.3                              0   benzyl    benzyl    2-propyl methyl  Bn                                    0   phenylethyl                                                                              phenylethyl                                                                              2-butyl  hydrogen                                                                               CH.sub.3                              0   blocked   blocked   benzyl   hydrogen                                                                               Bn                                        amino-    amino-                                                               methyl    methyl                                                           0   methyl-   methyl-   blocked  methyl  CH.sub.3                                  carbonyl- carbonyl- 4-hydroxy-                                                 ethyl     ethyl     phenylmethyl                                           0   PhtN-     PhtN-     blocked 3-                                                                              2-propyl                                                                               Bn                                        methyl    methyl    indolylmethyl    CH.sub.3                              0   PhtN-ethyl                                                                               PhtN-ethyl                                                                               4-methoxy-                                                                              2-butyl CH.sub.3                                                      phenylmethyl                                           0   TsNH-     TsNH-     phenylethyl                                                                             2-methyl-                                                                              Bn                                        methyl    methyl             propyl                                        1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     hydrogen   blocked 4-                                                                             CH.sub.3                                                               aminobutyl                                      1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     methyl     blocked 3-                                                                             Bn                                                                     guanyl-                                                                        propyl                                          1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-propyl   blocked 4-                                                                             CH.sub.3                                                               imidazoyl-                                                                     methyl                                          1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-butyl    benzyl  Bn                                      1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     benzyl     blocked 4-                                                                             CH.sub.3                                                               hydroxy-                                                                       phenyl-                                                                        methyl                                          1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     blocked    blocked 3-                                                                             Bn                                                          4-hydroxy- indolyl-                                                            phenylmethyl                                                                              methyl                                          1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     blocked 3- 4-methoxy-                                                                             CH.sub.3                                                    indolylmethyl                                                                             phenyl-                                                                        methyl                                          1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     4-methoxy- phenylethyl                                                                            Bn                                                          phenylmethyl                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                     phenylethyl                                                                               phenylethyl                                                                            CH.sub.3                                1   methyl    methyl    hydrogen 4-methoxy-                                                                             Bn                                                                     phenyl-                                                                        methyl                                        1   n-butyl   n-butyl   methyl   blocked 3-                                                                             CH.sub.3                                                               indolyl-                                                                       methyl                                        1   benzyl    benzyl    2-propyl blocked 4-                                                                             Bn                                                                     hydroxy-                                                                       phenyl-                                                                        methyl                                        1   phenylethyl                                                                              phenylethyl                                                                              2-butyl  benzyl  CH.sub.3                              1   blocked   blocked   benzyl   blocked 4-                                                                             Bn                                        amino-    amino-             imidazoyl-                                        methyl    methyl             methyl                                        1   methyl-   methyl-   blocked  blocked 3-                                                                             CH.sub.3                                  carbonyl- carbonyl- 4-hydroxy-                                                                              guanyl-                                           ethyl     ethyl     phenylmethyl                                                                            propyl                                        1   PhtN-     PhtN-     blocked 3-                                                                              blocked 4-                                                                             Bn                                        methyl    methyl    indolylmethyl                                                                           aminobutyl                                    1   PhtN-ethyl                                                                               PhtN-ethyl                                                                               4-methoxy-                                                                              2-methyl-                                                                              CH.sub.3                                                      phenylmethyl                                                                            propyl                                        1   TsNH-     TsNH-     phenylethyl                                                                             2-butyl Bn                                        methyl    methyl                                                           ______________________________________                                    

    __________________________________________________________________________     Formula 7                                                                       ##STR53##                                                                     where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       n R.sup.1                                                                               R.sup.2                                                                               R.sup.3                                                                               R.sup.4                                                                               R.sup.6                                          __________________________________________________________________________     0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   hydrogen                                                                              phenylethyl                                                                           hydrogen                                         0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   methyl 4-methoxy-                                                                            2-propyl                                                                phenylmethyl                                            0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-propyl                                                                              blocked 3-                                                                            methyl                                                                  indolyl-                                                                       methyl                                                  0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-butyl                                                                               blocked 4-                                                                            2-butyl                                                                 hydroxy-                                                                       phenylmethyl                                            0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-methyl-                                                                             benzyl 2-methyl-                                                        propyl        propyl                                           0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   blocked                                                                               blocked 4-                                                                            blocked 4-                                                       4-hydroxy-                                                                            imidazoyl-                                                                            aminobutyl                                                       phenylmethyl                                                                          methyl                                                  0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   blocked                                                                               blocked 3-                                                                            blocked 3-                                                       3-indolyl-                                                                            guanylpropyl                                                                          guanylpropyl                                                     methyl                                                         0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   4-methoxy-                                                                            blocked 4-                                                                            2-imidazoyl-                                                     phenylmethyl                                                                          aminobutyl                                                                            methyl                                           0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   phenylethyl                                                                           2-methyl-                                                                             hydroxy-                                                                propyl methyl                                           0 methyl methyl hydrogen                                                                              2-butyl                                                                               1-hydroxy-                                                                     ethyl                                            0 n-butyl                                                                               n-butyl                                                                               methyl 2-propyl                                                                              thiolmethyl                                      0 benzyl benzyl 2-propyl                                                                              methyl methylthio-                                                                    ethyl                                            0 phenylethyl                                                                           phenylethyl                                                                           2-butyl                                                                               hydrogen                                                                              methylthio-                                                                    ethyl                                            0 blocked                                                                               blocked                                                                               benzyl hydrogen                                                                              thiolmethyl                                        aminomethyl                                                                           aminomethyl                                                           0 methyl-                                                                               methyl-                                                                               blocked                                                                               methyl 1-hydroxy-                                         carbonyl-                                                                             carbonyl-                                                                             4-hydroxy-    ethyl                                              ethyl  ethyl  phenylmethyl                                                   0 PhtN-methyl                                                                           PhtN-methyl                                                                           blocked                                                                               2-propyl                                                                              hydroxy-                                                         3-indolyl-    methyl                                                           methyl                                                         0 PhtN-ethyl                                                                            PhtN-ethyl                                                                            4-methoxy-                                                                            2-butyl                                                                               2-imidazoyl-                                                     phenylmethyl  methyl                                           0 TsNH-methyl                                                                           TsNH-methyl                                                                           phenylethyl                                                                           2-methyl-                                                                             blocked 3-                                                              propyl guanylpropyl                                     1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   hydrogen                                                                              blocked 4-                                                                            blocked 4-                                                       aminobutyl                                                                            aminobutyl                                              1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   methyl blocked 3-                                                                            2-methyl-                                                               guanylpropyl                                                                          propyl                                           1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-propyl                                                                              blocked 4-                                                                            2-butyl                                                                 imidazoyl-                                                                     methyl                                                  1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-butyl                                                                               benzyl methyl                                           1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   benzyl blocked 4-                                                                            2-propyl                                                                hydroxy-                                                                       phenylmethyl                                            1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   blocked                                                                               blocked 3-                                                                            hydrogen                                                         4-hydroxy-                                                                            indolylmethy                                                            phenylmethyl                                                   1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   blocked                                                                               4-methoxy-                                                                            methylthio-                                                      3-indolyl-                                                                            phenylmethyl                                                                          ethyl                                                            methyl                                                         1 CH.sub.2 2CH.sub.2 CH.sub.2                                                                  4-methoxy-                                                                            phenylethyl                                                                           thiolmethyl                                                      phenylmethyl                                                   1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   phenylethyl                                                                           phenylethyl                                                                           1-hydroxy-                                                                     ethyl                                            1 methyl methyl hydrogen                                                                              4-methoxy-                                                                            hydroxy-                                                                phenylmethyl                                                                          methyl                                           1 n-butyl                                                                               n-butyl                                                                               methyl blocked 3-                                                                            2-imidazoyl-                                                            indolylmethyl                                                                         methyl                                           1 benzyl benzyl 2-propyl                                                                              blocked 4-                                                                            blocked 3-                                                              hydroxy-                                                                              guanylpropyl                                                            phenylmethyl                                            1 phenylethyl                                                                           phenylethyl                                                                           2-butyl                                                                               benzyl blocked 4-                                                                     aminobutyl                                       1 blocked                                                                               blocked                                                                               benzyl blocked 4-                                                                            2-methyl-                                          aminomethyl                                                                           aminomethyl   imidazoyl-                                                                            propyl                                                                  methyl                                                  1 methyl-                                                                               methyl-                                                                               blocked                                                                               blocked 3-                                                                            2-butyl                                            carbonyl-                                                                             carbonyl-                                                                             4-hydroxy-                                                                            guanylpropyl                                              ethyl  ethyl  phenylmethyl                                                   1 PhtN-methyl                                                                           PhtN-methyl                                                                           blocked                                                                               blocked 4-                                                                            methyl                                                           3-indolyl-                                                                            aminobutyl                                                              methyl                                                         1 PhtN-ethyl                                                                            PhtN-ethyl                                                                            4-methoxy-                                                                            2-methyl-                                                                             2-propyl                                                         phenylmethyl                                                                          propyl                                                  1 TsNH-methyl                                                                           TsNH-methyl                                                                           phenylethyl                                                                           2-butyl                                                                               hydrogen                                         __________________________________________________________________________

EXAMPLE 5 Preparation of HS(CH₂)₂ --(S-D-Leu)-Phe-NHMe

5A. Formula I Where n Is 0, R¹ and R² Are Hydrogen, R³ Is 2-Methylpropyl and R⁴ Is Phe-NHMe

To a solution of 4.14 g of BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-Phe-NHMe in 150 mL of MeOH and 20 mL of water was added 2.63 g of Hg(OAc)₂. The mixture was stirred at room temperature for 1 h, then H₂ S gas was bubbled through the mixture for 15 min. Water was added and the precipitate was removed by filtration. The filtrate was extracted thoroughly with EtOAc and the combined extract was washed with water and dried over Na₂ SO₄. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (5% EtOAc in CH₂ Cl₂) to give 2.18 g of HS(CH₂)₂ --(S-D-Leu)-Phe-NHMe as a solid at 72% yield. Characteristic analytical data are as follows: mp 169°-171° C. (hexane-EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ7.20-7.34 (m, 5H), 7.00 (br d, J=8 Hz, 1H, NH), 5.90 (br s, 1H, NH), 4.60 (q, J=8 Hz, 1H), 3.27 (dd, J=7, 8 Hz, 1H), 3.15 (dd, J=7, 14 Hz, 1H), 3.07 (dd, J=8, 14 Hz, 1H), 2.75 (d, J=5 Hz, 3H), 2.55 (m, 2H), 2.43 (m, 2H), 1.62-1.73 (m, 2H), 1.59 (t, J=8 Hz, 1H, S 1.40-1.52 (m, 1H), 0.89 (d, J=7 Hz, 3H), 0.88 (d, J=7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl₃) δ172.9 (C), 171.6 (C), 136.9 (C), 129.4 (CH), 128.9 (CH), 127.2 (CH), 54.5 (CH), 47.9 (CH), 41.2 (CH₂), 37.8 (CH₂), 35.0 (CH₂), 26.0 (CH₃), 25.8 (CH₃), 24.2 (CH₂), 22.3 (CH₃), 21.7 (CH₃); [α]_(D) ²⁵ +39.7° (c=0.32, MeOH). Anal. Calcd for C₁₈ H₂₈ N₂ O₂ S₂ : C, 58.66; H, 7.66; N, 7.60; S, 17.40. Found: C, 58.76; H, 7.69; N, 7.54; S, 17.46.

5B. Preparation of the Corresponding (S-L-Leu) Isomer of Formula I

The BzNHCH₂ S(CH₂)₂ --(S-L-Leu)-Phe-NHMe was deblocked as described above for the D-isomer to afford HS(CH₂)₂ --(S-L-Leu)-Phe-NHMe as a solid (48% yield): mp 156°-158° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.19-7.32 (m, 6H), 6.19 (br m, 1H, NH), 4.64 (q, J=8 Hz, 1H), 3.32 (t, J=8 Hz, 1H), 3.11 (dd, J=7, 14 Hz, 1H), 3.05 (dd, J=8, 14 Hz, 1H), 2.75 (d, J=5 Hz, 3H), 2.60-2.70 (m, 4H), 1.47-1.68 (m, 3H), 1.32-1.44 (m, 1H), 0.87 (d, J=6 Hz, 3H), 0.83 (d, J=6 Hz, 3H [α]_(D) ²⁵ -61° (c=0.10, MeOH).

5C. Formula I Varying R³

By following the procedures described in Example 5A and substituting BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 7 (where the R⁵ substituents are as indicated in the table below) there are obtained the correspondingly substituted of compounds of Formula I.

    ______________________________________                                         Formula I                                                                       ##STR54##                                                                     where R.sup.4 is phenylmethyl and R.sup.5 is methyl                            R.sup.3  Name                                                                  ______________________________________                                         hydrogen HS(CH.sub.2).sub.2 (SGly)PheNHMe                                      methyl   HS(CH.sub.2).sub.2 (S-D-Ala)Phe NHMe                                  2-propyl HS(CH.sub.2).sub.2 (S-D-Val)PheNHMe                                   2-butyl  HS(CH.sub.2).sub.2 (S-D-Ile)PheNHMe                                   benzyl   HS(CH.sub.2).sub.2 (S-D-Phe)PheNHMe                                   4-hydroxy-                                                                              HS(CH.sub.2).sub.2 (S-D-Tyr)PheNHMe                                   phenylmethyl                                                                   3-indolyl-                                                                              HS(CH.sub.2).sub.2 (S-D-Trp)PheNHMe                                   methyl                                                                         4-methoxy-                                                                              HS(CH.sub.2).sub.2 (S-D-TyrOCH.sub.3)PheNHMe                          phenylmethyl                                                                   phenylethyl                                                                             HS(CH.sub.2).sub.2 (S-D-Phet)PheNHMe                                  ______________________________________                                    

5D. Formula I Varying R³

By following the procedures described in Example 5B and substituting BzNHCH₂ S(CH₂)₂ --(S-L-Leu)-Phe-NHMe with other compounds of Formula 7 (where the substituents are as indicated in the table below) there are obtained the correspondingly substituted of compounds of Formula I.

    ______________________________________                                         Formula I                                                                       ##STR55##                                                                     where R.sup.4 is phenylmethyl and R.sup.5 is methyl                            R.sup.3  Name                                                                  ______________________________________                                         methyl   HS(CH.sub.2).sub.2 (S-L-Ala)PheNHMe                                   2-propyl HS(CH.sub.2).sub.2 (S-L-Val)pheNHMe                                   2-butyl  HS(CH.sub.2).sub.2 (S-L-Ile)PheNHMe                                   benzyl   HS(CH.sub.2).sub.2 (S-L-Phe)PheNHMe                                   4-hydroxy-                                                                              HS(CH.sub.2).sub.2 (S-L-Tyr)PheNHMe                                   phenylmethyl                                                                   3-indolyl-                                                                              HS(CH.sub.2).sub.2 (S-L-Trp)PheNHMe                                   methyl                                                                         4-methoxy-                                                                              HS(CH.sub.2).sub.2 (S-L-TyrOCH.sub.3)PheNHMe                          phenylmethyl                                                                   phenylethyl                                                                             HS(CH.sub.2).sub.2 (S-L-Phet)PheNHMe                                  ______________________________________                                    

5E. Formula I Varying n, R¹, R² and R³

By following the procedures described in Example 5A and substituting BzNHCH₂ S(CH₂)₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 7 (e.g., compounds that are prepared according to Examples 4A-4F) there are obtained the correspondingly substituted of compounds of Formula I (where n, R¹, R², R³, R⁴, R⁵, and R⁶ are as indicated in the tables below).

    ______________________________________                                         Formula I                                                                       ##STR56##                                                                     where R.sup.4 is phenylmethyl and R.sup.5 is methyl                            n   R.sup.1     R.sup.2     R.sup.3                                            ______________________________________                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-methylpropyl                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-hydroxyphenylmethyl                                  0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         3-indolylmethyl                                        0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  0   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            0   methyl      methyl      hydrogen                                           0   n-butyl     n-butyl     methyl                                             0   benzyl      benzyl      2-propyl                                           0   phenylethyl phenylethyl 2-butyl                                            0   aminomethyl aminomethyl benzyl                                             0   methyl-     methyl-     4-hydroxyphenylmethyl                                  carbonylethyl                                                                              carbonylethyl                                                  0   PhtN-methyl PhtN-methyl 3-indolylmethyl                                    0   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              0   TsNH-methyl TsNH-methyl phenylethyl                                        1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         hydrogen                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         methyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-propyl                                               1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         2-butyl                                                1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         benzyl                                                 1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-hydroxyphenylmethyl                                  1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         3-indolylmethyl                                        1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         4-methoxyphenylmethyl                                  1   CH.sub.2 CH.sub.2 CH.sub.2                                                                         phenylethyl                                            1   methyl      methyl      hydrogen                                           1   n-butyl     n-butyl     methyl                                             1   benzyl      benzyl      2-propyl                                           1   phenylethyl phenylethyl 2-butyl                                            1   aminomethyl aminomethyl benzyl                                             1   methyl-     methyl-     4-hydroxyphenylmethyl                                  carbonylethyl                                                                              carbonylethyl                                                  1   PhtN-methyl PhtN-methyl 3-indolylmethyl                                    1   PhtN-ethyl  PhtN-ethyl  4-methoxyphenylmethyl                              1   TsNH-methyl TsNH-methyl phenylethyl                                        ______________________________________                                    

5F. Formula I Varying n, R^(l), R², R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 5A and substituting BzNHCH₂ S(CH₂)₂ -(S-D-Leu)-Phe-NHMe with other compounds of Formula 7 (e.g., compounds that are prepared according to Examples 4A-4F) there are obtained the correspondingly substituted compounds of Formula I (where n, R¹, R², R³, R⁴, R⁵ and R⁶ are as indicated in the tables below).

    ______________________________________                                         Formula I                                                                       ##STR57##                                                                     where R.sup.5 is methyl or phenylmethyl                                        n   R.sup.1   R.sup.2   R.sup.3 R.sup.4  R.sup.5                               ______________________________________                                         0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     hydrogen  phenylethyl                                                                             CH.sub.3                                0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     methyl    4-methoxy-                                                                              Bn                                                                    phenylmethyl                                     0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-propyl  3-indolyl-                                                                              CH.sub.3                                                              methyl                                           0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-butyl   4-hydroxy-                                                                              Bn                                                                    phenylmethyl                                     0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     2-methyl- benzyl   CH.sub.3                                                    propyl                                                     0   CH.sub. 2 CH.sub.2 CH.sub.2                                                                    4-hydroxy-                                                                               4-imidazoyl-                                                                            Bn                                                          phenyl-   methyl                                                               methyl                                                     0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     3-indolyl-                                                                               3-guanyl-                                                                               CH.sub.3                                                    methyl    propyl                                           0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     4-methoxy-                                                                               4-aminobutyl                                                                            Bn                                                          phenyl-                                                                        methyl                                                     0   CH.sub.2 CH.sub.2 CH.sub.2                                                                     phenylethyl                                                                              2-methyl-                                                                               CH.sub.3                                                              propyl                                           0   methyl   methyl   hydrogen  2-butyl  Bn                                    ______________________________________                                    

    __________________________________________________________________________     Formula I                                                                       ##STR58##                                                                     where R.sup.5 is methyl or phenylmethyl                                        n R.sup.1                                                                               R.sup.2 R.sup.3 R.sup.4 R.sup.5                                       __________________________________________________________________________     0 n-butyl                                                                               n-butyl methyl  2-propyl                                                                               CH.sub.3                                      0 benzyl benzyl  2-propyl                                                                               methyl  Bn                                            0 phenylethyl                                                                           phenylethyl                                                                            2-butyl hydrogen                                                                               CH.sub.3                                      0 aminomethyl                                                                           aminomethyl                                                                            benzyl  hydrogen                                                                               Bn                                            0 methyl-                                                                               methyl- 4-hydroxy-                                                                             methyl  CH.sub.3                                        carbonylethyl                                                                         carbonylethyl                                                                          phenylmethyl                                                  0 PhtN-methyl                                                                           PhtN-methyl                                                                            3-indolylmethyl                                                                        2-propyl                                                                               Bn                                            0 PhtN-ethyl                                                                            PhtN-ethyl                                                                             4-methoxy-                                                                             2-butyl CH.sub.3                                                       phenylmethyl                                                  0 TsNH-methyl                                                                           TsNH-methyl                                                                            phenylethyl                                                                            2-methyl-                                                                              Bn                                                                     propyl                                                1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    hydrogen                                                                               4-aminobutyl                                                                           CH.sub.3                                      1 CH.sub.2 CH.sub. 2 CH.sub.2                                                                   methyl  3-guanyl-                                                                              Bn                                                                     propyl                                                1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    2-propyl                                                                               4-imidazoyl-                                                                           CH.sub.3                                                               methyl                                                1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    2-butyl benzyl  Bn                                            1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    benzyl  4-hydroxy-                                                                             CH.sub.3                                                               phenylmethyl                                          1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    4-hydroxy-                                                                             3-indolyl-                                                                             Bn                                                             phenylmethyl                                                                           methyl                                                1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    3-indolylmethyl                                                                        4-methoxy-                                                                             CH.sub.3                                                               phenylmethyl                                          1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    4-methoxy-                                                                             phenylethyl                                                                            Bn                                                             phenylmethyl                                                  1 CH.sub.2 CH.sub.2 CH.sub.2                                                                    phenylethyl                                                                            phenylethyl                                                                            CH.sub.3                                      1 methyl methyl  hydrogen                                                                               4-methoxy-                                                                             Bn                                                                     phenylmethyl                                          1 n-butyl                                                                               n-butyl methyl  3-indolyl-                                                                             CH.sub.3                                                               methyl                                                1 benzyl benzyl  2-propyl                                                                               4-hydroxy-                                                                             Bn                                                                     phenylmethyl                                          1 phenylethyl                                                                           phenylethyl                                                                            2-butyl benzyl  CH.sub.3                                      1 aminomethyl                                                                           aminomethyl                                                                            benzyl  4-imidazoyl-                                                                           Bn                                                                     methyl                                                1 methyl-                                                                               methyl- 4-hydroxy-                                                                             3-guanyl-                                                                              CH.sub.3                                        carbonylethyl                                                                         carbonylethyl                                                                          phenylmethyl                                                                           propyl                                                1 PhtN-methyl                                                                           PhtN-methyl                                                                            3-indolylmethyl                                                                        4-aminobutyl                                                                           Bn                                            1 PhtN-ethyl                                                                            PhtN-ethyl                                                                             4-methoxy-                                                                             2-methyl-                                                                              CH.sub.3                                                       phenylmethyl                                                                           propyl                                                1 TsNH-methyl                                                                           TsNH-methyl                                                                            phenylethyl                                                                            2-butyl Bn                                            __________________________________________________________________________

    __________________________________________________________________________     Formula I                                                                       ##STR59##                                                                     where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       n R.sup.1                                                                               R.sup.2                                                                               R.sup.3                                                                               R.sup.4                                                                               R.sup.6                                          __________________________________________________________________________     0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   hydrogen                                                                              phenylethyl                                                                           hydrogen                                         0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   methyl 4-methoxy-                                                                            2-propyl                                                                phenylmethyl                                              CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-propyl                                                                              3-indolyl-                                                                            methyl                                                                  methyl                                                  0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-butyl                                                                               4-hydroxy-                                                                            2-butyl                                                                 phenylmethyl                                            0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-methyl-                                                                             benzyl 2-methyl-                                                        propyl        propyl                                           0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   4-hydroxy-                                                                            4-imidazoyl-                                                                          4-aminobutyl                                                     phenylmethyl                                                                          methyl                                                  0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   3-indolyl-                                                                            3-guanyl-                                                                             3-guanyl-                                                        methyl propyl propyl                                           0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   4-methoxy-                                                                            4-aminobutyl                                                                          2-imidazoyl-                                                     phenylmethyl  methyl                                           0 CH.sub.2 CH.sub.2 CH.sub.2                                                                   phenylethyl                                                                           2-methyl-                                                                             hydroxy-                                                                propyl methyl                                           0 methyl methyl hydrogen                                                                              2-butyl                                                                               1-hydroxy-                                                                     ethyl                                            0 n-butyl                                                                               n-butyl                                                                               methyl 2-propyl                                                                              thiolmethyl                                      0 benzyl benzyl 2-propyl                                                                              methyl methylthio-                                                                    ethyl                                            0 phenylethyl                                                                           phenylethyl                                                                           2-butyl                                                                               hydrogen                                                                              methylthio-                                                                    ethyl                                            0 aminomethyl                                                                           aminomethyl                                                                           benzyl hydrogen                                                                              thiolmethyl                                      0 methyl-                                                                               methyl-                                                                               4-hydroxy-                                                                            methyl 1-hydroxy-                                         carbonyl-                                                                             carbonyl-                                                                             phenylmethyl  ethyl                                              ethyl  ethyl                                                                 0 PhtN-methyl                                                                           PhtN-methyl                                                                           3-indolyl-                                                                            2-propyl                                                                              hydroxy-                                                         methyl        methyl                                           0 PhtN-ethyl                                                                            PhtN-ethyl                                                                            4-methoxy-                                                                            2-butyl                                                                               2-imidazoyl-                                                     phenylmethyl  methyl                                           0 TsNH-methyl                                                                           TsNH-methyl                                                                           phenylethyl                                                                           2-methyl-                                                                             3-guanyl-                                                               propyl propyl                                           1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   hydrogen                                                                              4-aminobutyl                                                                          4-aminobutyl                                     1 CH.sub. 2 CH.sub.2 CH.sub.2                                                                  methyl 3-guanyl-                                                                             2-methyl-                                                               propyl propyl                                           1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-propyl                                                                              4-imidazoyl-                                                                          2-butyl                                                                 methyl                                                  1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   2-butyl                                                                               benzyl methyl                                           1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   benzyl 4-hydroxy-                                                                            2-propyl                                                                phenylmethyl                                            1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   4-hydroxy-                                                                            3-indolyl-                                                                            hydrogen                                                         phenylmethyl                                                                          methyl                                                  1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   3-indolyl-                                                                            4-methoxy-                                                                            methylthio-                                                      methyl phenylmethyl                                                                          ethyl                                            1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   4-methoxy-                                                                            phenylethyl                                                                           thiolmethyl                                                      phenylmethyl                                                   1 CH.sub.2 CH.sub.2 CH.sub.2                                                                   phenylethyl                                                                           phenylethyl                                                                           1-hydroxy-                                                                     ethyl                                            1 methyl methyl hydrogen                                                                              4-methoxy-                                                                            hydroxy-                                                                phenylmethyl                                                                          methyl                                           1 n-butyl                                                                               n-butyl                                                                               methyl 3-indolyl-                                                                            2-imidazoyl-                                                            methyl methyl                                           1 benzyl benzyl 2-propyl                                                                              4-hydroxy-                                                                            3-guanyl-                                                               phenylmethyl                                                                          propyl                                           1 phenylethyl                                                                           phenylethyl                                                                           2-butyl                                                                               benzyl 4-aminobutyl                                     1 aminomethyl                                                                           aminomethyl                                                                           benzyl 4-imidazoyl-                                                                          2-methyl-                                                               methyl propyl                                           1 methyl-                                                                               methyl-                                                                               4-hydroxy-                                                                            3-guanyl-                                                                             2-butyl                                            carbonyl-                                                                             carbonyl-                                                                             phenylmethyl                                                                          propyl                                                    ethyl  ethyl                                                                 1 PhtN-methyl                                                                           PhtN-methyl                                                                           3-indolyl-                                                                            4-aminobutyl                                                                          methyl                                                           methyl                                                         1 PhtN-ethyl                                                                            PhtN-ethyl                                                                            4-methoxy-                                                                            2-methyl-                                                                             2-propyl                                                         phenylmethyl                                                                          propyl                                                  1 TsNH-methyl                                                                           TsNH-methyl                                                                           phenylethyl                                                                           2-butyl                                                                               hydrogen                                         __________________________________________________________________________

EXAMPLE 6 Preparation of (2R)-2-Bromopropanoic Acid

6A. Formula 9 Where R¹ Is Methyl and X Is Bromo

To a stirred solution of 5.00 g of D-Ala, 23.4 g of KBr in 37 mL of water and 11 mL of conc. sulfuric acid at -8° C. was added a solution of 5.14 g of NaNO₂ in 2 mL of water over a period of 1 h. Stirring was continued for 1 h at the same temperature, the reaction mixture was then extracted with CH₂ Cl₂. The organic layer was washed with water, dried over Na₂ SO₄ and evaporated under vacuum to give 3.16 g of (2R)-2-bromopropanoic acid as an oil at 41% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ4.41 (q, J=7 Hz, 1H), 1.86 (d, J=7 Hz, 3H); [α]_(D) ²⁵ +32.6° (c=2.10, MeOH).

6B. Preparation of the Corresponding (S) Isomer of Formula 9

By following the procedure described in Example 6A and substituting L-Ala for D-Ala, (2S)-2-Bromopropanoic acid was obtained in 43% yield. Characteristic analytical data are as follows: [α]_(D) ²⁵ -31.8° (c=2.10, MeOH).

6C. Formula 9 Varying R¹

By following the procedures described in Example 6A and substituting D-Ala with other compounds of Formula 8 and KBr with other halo salts there are obtained the correspondingly substituted compounds of Formula 9 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 9                                                                       ##STR60##                                                                     X   R.sup.1      Name                                                          ______________________________________                                         Cl  hydrogen     2-chloroethanoic acid                                         I   2-propyl     (2R)-2-iodo-3-methylbutanoic acid                             Br  2-methylpropyl                                                                              (2R)-2-bromo-4-methylpentanoic acid                           Cl  2-butyl      (2R)-2-chloro-3-methylpentanoic acid                          Br  blocked      (2R)-6-amino-2-bromohexanoic acid                                 aminobutyl                                                                 Cl  carbamoylmethyl                                                                             (2R)-3-carbamoyl-2-chloropropanoic acid                       ______________________________________                                    

6D. Formula 9 Varying R¹

By following the procedures described in Example 6A and substituting L-Ala with other compounds of Formula 8 and KBr with other halo salts there are obtained the correspondingly substituted compounds of Formula 9 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 9                                                                       ##STR61##                                                                     X   R.sup.1      Name                                                          ______________________________________                                         I   2-propyl     (2S)-2-iodo-3-methylbutanoic acid                             Br  2-methylpropyl                                                                              (2S)-2-bromo-4-methylpentanoic acid                           Cl  2-butyl      (2S)-2-chloro-3-methylpentanoic acid                          Br  blocked      (2S)-6-amino-2-bromohexanoic acid                                 aminobutyl                                                                 Cl  carbamoylmethyl                                                                             (2S)-3-carbamoyl-2-chloropropanoic acid                       ______________________________________                                    

EXAMPLE 7 Preparation of (2S)-2-(Tert-Butylthio)Propanoic Acid

7A. Formula 10 Where R¹ Is Methyl

To a solution of 483 mg of Na in 10 mL of EtOH was added 10 mL of tert-butylthiol with stirring at room temperature under nitrogen. After 10 min a solution of 1.53 g of (2R)-2-bromopropanoic acid in 3 mL of EtOH was added and the stirring was continued at room temperature for 3 h. The reaction mixture was poured into water and was acidified with acetic acid and extracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and was evaporated under water aspirator vacuum using a trap containing bleach to give 1.48 g of (2S)-2-(tert-butylthio)propanoic acid as an oil at 92% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ3.44 (q, J=7 Hz, 1H), 1.49 (d, J=7 Hz, 3H), 1.37 (s, 9H).

7B. Preparation of the Corresponding (R) Isomer of Formula 10

By the following procedure described in Example 7A and substituting (2R)-2-bromopropanoic acid with (2S)-2-bromopropanoic acid, (2R)-2-(tert-butylthio)propanoic acid was obtained at 93% yield.

7C. Formula 10 Varying R¹

By following the procedures described in Example 7A and substituting (2R)-2-bromopropanoic acid with other compounds of Formula 9 there are obtained the correspondingly substituted compounds of Formula 10 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 10                                                                      ##STR62##                                                                     R.sup.1    Name                                                                ______________________________________                                         hydrogen   2-(t-butylthio)ethanoic acid                                        2-propyl   (2S)-2-(t-butylthio)-3-methylbutanoic acid                          2-methylpropyl                                                                            (2S)-2-(t-butylthio)-4-methylpentanoic acid                         2-butyl    (2S)-2-(t-butylthio)-3-methylpentanoic acid                         blocked    (2S)-6-amino-2-(t-butylthio)hexanoic acid                           aminobutyl                                                                     carbamoylmethyl                                                                           (2S)-3-carbamoyl-2-(t-butylthio)propanoic acid                      ______________________________________                                    

7D. Formula 10 Varying R¹

By following the procedures described in Example 7B and substituting (2S)-2-bromopropanoic acid with other compounds of Formula 9 there are obtained the correspondingly substituted compounds of Formula 10 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 10                                                                      ##STR63##                                                                     R.sup.1    Name                                                                ______________________________________                                         2-propyl   (2R)-2-(t-butylthio)-3-methylbutanoic acid                          2-methylpropyl                                                                            (2R)-2-(t-butylthio)-4-methylpentanoic acid                         2-butyl    (2R)-2-(t-butylthio)-3-methylpentanoic acid                         blocked    (2R)-6-amino-2-(t-butylthio)hexanoic acid                           aminobutyl                                                                     carbamoylmethyl                                                                           (2R)-3-carbamoyl-2-(t-butylthio)propanoic acid                      ______________________________________                                    

EXAMPLE 8 Preparation of (2S)-2-(t-Butylthio)-1-Propanol

8A. Formula 11 Where R¹ Is Methyl

To a stirred solution of 1.47 g of the (2S)-2-(t-butylthio)propanoic acid in 22 mL of THF at 0° C. was added dropwise 22 mL of 1M borane/THF over a period of 15 min. Stirring was continued at room temperature for 3 h. The reaction was quenched by dropwise addition of cold water. The mixture was extracted with ether. The organic layer was washed with saturated NaHCO₃, saturated NaCl solution and dried over Na₂ SO₄. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (10% EtOAc in hexane) to give 1.10 g of (2S)-2-(tert-butylthio)-1-propanol as an oil at 82% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ3.61 (ddd, J=5, 9, 11 Hz, 1H), 3.33 (ddd, J=4, 8, 11 Hz, 1H), 2.89 (m, 1H), 2.31 (dd, J= 4, 9 Hz, 1H, OH), 1.36 (s, 9H), 1.30 (d, J=7 Hz, 3H); [α]_(D) ²⁵ -10.3° (c=2.04, MeOH).

8B. Preparation of the Corresponding (2R) Isomer of Formula 11

By following the procedure described in Example 8A and substituting (2S)-2-(t-butylthio)propanoic acid with (2R)-2-(t-butylthio)propanoic acid, (2R)-2-(t-butylthio)-1-propanol was obtained at 89% yield. Characteristic analytical data are as follows: [α]_(D) ²⁵ +9.8° (c=2.02, MeOH).

8C. Formula 11 Varying R¹

By following the procedures described in Example 8A and substituting (2S)-2-(t-butylthio)propanoic acid with other compounds of Formula 10 there are obtained the correspondingly substituted of compounds of Formula 11 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 11                                                                      ##STR64##                                                                     R.sup.1     Name                                                               ______________________________________                                         hydrogen    2-(t-butylthio)ethanol                                             2-propyl    (2S)-2-(t-butylthio)-3-methylbutanol                               2-methylpropyl                                                                             (2S)-2-(t-butylthio)-4-methylpentanol                              2-butyl     (2S)-2-(t-butylthio)-3-methylpentanol                              blocked aminoethyl                                                                         (2S)-4-amino-2-(t-butylthio)butanol                                blocked aminobutyl                                                                         (2S)-6-amino-2-(t-butylthio)hexanol                                carbamoylmethyl                                                                            (2S)-3-carbamoyl-2-(t-butylthio)propanol                           ______________________________________                                    

8D. Formula 11 Varying R¹

By following the procedures described in Example 8B and substituting (2R)-2-(t-butylthio)propanoic acid with other compounds of Formula 10 there are obtained the correspondingly substituted of compounds of Formula 11 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 11                                                                      ##STR65##                                                                     R.sup.1     Name                                                               ______________________________________                                         2-propyl    (2R)-2-(t-butylthio)-3-methylbutanol                               2-methylpropyl                                                                             (2R)-2-(t-butylthio)-4-methylpentanol                              2-butyl     (2R)-2-(t-butylthio)-3-methylpentanol                              blocked aminoethyl                                                                         (2R)-4-amino-2-(t-butylthio)butanol                                blocked aminobutyl                                                                         (2R)-6-amino-2-(t-butylthio)hexanol                                carbamoylmethyl                                                                            (2R)-3-carbamoyl-2-(t-butylthio)propanol                           ______________________________________                                    

EXAMPLE 9 Preparation of (2S)-1-(Acetylthio)-2-(t-Butylthio)Propane

9A. Formula 12 Where R¹ Is Methyl

To a stirred solution of 3.54 g of triphenylphosphine in 50 mL of THF at 0° C. was added 2.66 mL of diisopropyl azodicarboxylate. The mixture was stirred for an additional 30 min. To the resulting white precipitate was added 1.00 g of (2S)-2-(t-butylthio)-1-propanol in 5 mL of THF. The reaction mixture was stirred for 10 min, then 0.966 mL of thiolacetic acid was added and stirring was continued at 0° C. for 1 h and at room temperature for 1 h. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (5% CH₂ Cl₂ in hexane) to give 1.16 g of (2S)-1-(acetylthio)-2-(t-butylthio)propane as an oil at 83% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ3.32 (m, 1H), 2.8-2.94 (m, 2H), 2.35 (s, 3 H), 1.38 (s, 9H), 1.33 (d, J=7 Hz, 3H).

9B. Preparation of the Corresponding (2R) Isomer of Formula 12

By following the procedure described in Example 9A and substituting (2S)-2-(t-butylthio)-1-propanol with (2R)-2-(t-butylthio)-1-propanol, (2R)-1-(acetylthio)-2-(t-butylthio)propane was obtained as an oil at 70% yield.

9C. Formula 12 Varying R¹

By following the procedures described in Example 9A and substituting (2S)-2-(t-butylthio)-1-propanol with other compounds of Formula 11 there are obtained the correspondingly substituted of compounds of Formula 12 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 12                                                                      ##STR66##                                                                     R.sup.1  Name                                                                  ______________________________________                                         hydrogen 1-(acetylthio)-2-(t-butylthio)ethane                                  2-propyl (2S)-1-(acetylthio)-2-(t-butylthio)-3-methylbutane                    2-methyl-                                                                               (2S)-1-(acetylthio)-2-(t-butylthio)-4-methylpentane                   propyl                                                                         2-butyl  (2S)-1-(acetylthio)-2-(t-butylthio)-3-methylpentane                   blocked  (2S)-1-(acetylthio)-4-amino-2-(t-butylthio)butane                     aminoethyl                                                                     blocked  (2S)-1-(acetylthio)-6-amino-2-(t-butylthio)hexane                     aminobutyl                                                                     carbamoyl-                                                                              (2S)-1-(acetylthio)-3-carbamoyl-2-(t-                                 methyl   butylthio)propane                                                     ______________________________________                                    

9D. Formula 12 Varying R¹

By following the procedures described in Example 9B and substituting (2R)-2-(t-butylthio)-1-propanol with other compounds of Formula 11 there are obtained the correspondingly substituted of compounds of Formula 12 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 12                                                                      ##STR67##                                                                     R.sup.1  Name                                                                  ______________________________________                                         2-propyl (2R)-1-(acetylthio)-2-(t-butylthio)-3-methylbutane                    2-methyl-                                                                               (2R)-1-(acetylthio)-2-(t-butylthio)-4-methylpentane                   propyl                                                                         2-butyl  (2R)-1-(acetylthio)-2-(t-butylthio)-3-methylpentane                   blocked  (2R)-1-(acetylthio)-4-amino-2-(t-butylthio)butane                     aminoethyl                                                                     blocked  (2R)-1-(acetylthio)-6-amino-2-(t-butylthio)hexane                     aminobutyl                                                                     carbamoyl-                                                                              (2R)-1-(acetylthio)-3-carbamoyl-2-(t-                                 methyl   butylthio)propane                                                     ______________________________________                                    

EXAMPLE 10 Preparation of t-BuS(S)CHMeCH₂ --(S-D-Leu)-OH

10A. Formula 14 Where R¹ Is Methyl and R³ Is 2-Methylpropyl

To a solution of 46 mg of Na in 2 mL of EtOH was added a solution of mg of (2S)-1-(acetylthio)-2-(t-butylthio)propane in 1 mL of EtOH with stirring at room temperature under nitrogen. After 5 min a solution of 170 mg of (2S)-2-bromo-4-methylpentanoic acid in 1 mL of EtOH was added and stirring was continued at room temperature for 4 h. The reaction mixture was poured into water, acidified with acetic acid and extracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum. Purification of the residue by flash chromatography (15% EtOAc in hexane) afforded 146 mg of t-BuS(S)CHMeCH₂ --(S-D-Leu)-OH as a colorless gum at 60% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ3.72 (t, J=7 Hz, 1H), 3.01 (dd, J=5, 12 Hz, 1H), 2.88-2.98 (m, 1H), 2.76 (dd, J=8, 12 Hz, 1H), 1.73-1.85 (m, 2H), 1.55 (m, 1H), 1.39 (d, J=7 Hz, 3H), 1.35 (s 9H), 0.95 (d, J=7 Hz, 3H), 0.93 (d, J=7 Hz, 3H); [α]_(D) ²⁵ +2.3° (c=0.86, MeOH).

10B. Preparation of the Corresponding (2R) Isomer of Formula 14

By following the procedure described in Example 10A and substituting (2S) -1- (acetylthio) -2- (t-butylthio)propane with (2R) -1-(acetylthio)-2-(t-butylthio)propane, t-BuS(R)CHMeCH₂ --(S-D-Leu)-OH was obtained as a colorless gum at 51% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ3.36 (t, J=7 Hz, 1H), 3.08 (dd, J=5, 13 Hz, 1H), 2.87-2.96 (m, 1H), 2.66 (dd, J=9, 13 Hz, 1H), 1.72-1.85 (m, 2H), 1.55 (m, 1H), 1.39 (d, J=7 Hz, 3H), 1.35 (s, 9H), 0.95 (d, J=6 Hz, 3H), 0.93 (d, J=6 Hz, 3H); [α]_(D) ²⁵ +121° (c=0.88, MeOH).

10C. Formula 14 Varying R¹

By following the procedures described in Example 10A and substituting (2S)-1-(acetylthio)-2-(t-butylthio)propane with other compounds of Formula 12 there are obtained the correspondingly substituted of compounds of Formula 14 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 14                                                                      ##STR68##                                                                     where R.sup.3 is 2-methylpropyl                                                R.sup.1 Name                                                                   ______________________________________                                         hydrogen                                                                               t-BuSCH.sub.2 CH.sub.2 (S-D-Leu)OH                                     2-propyl                                                                               t-BuS(S)CH(2-propyl)CH.sub.2 (S-D-Leu)OH                               2-methyl-                                                                              t-BuS(S)CH(2-methylpropyl)CH.sub.2 (S-D-Leu)OH                         propyl                                                                         2-butyl t-BuS(S)CH(2-butyl)CH.sub.2 (S-D-Leu)OH                                blocked t-BuS(S)CH(aminoethyl)CH.sub.2 (S-D-Leu)OH                             aminoethyl                                                                     blocked t-BuS(S)CH(aminobutyl)CH.sub.2 (S-D-Leu)OH                             aminobutyl                                                                     carbamoyl-                                                                             t-BuS(S)CH(carbamoyl-                                                  methyl  methyl)CH.sub.2 (S-D-Leu)OH                                            ______________________________________                                    

10D. Formula 14 Varying R¹

By following the procedures described in Example 10B and substituting (2R)-1-(acetylthio)-2-(t-butylthio)propane with other compounds of Formula 12 there are obtained the correspondingly substituted of compounds of Formula 14 (where R¹ is as indicated in the table below).

    ______________________________________                                         Formula 14                                                                      ##STR69##                                                                     where R.sup.3 is 2-methylpropyl                                                R.sup.1 Name                                                                   ______________________________________                                         2-propyl                                                                               t-BuS(R)CH(2-propyl)CH.sub.2 (S-D-Leu)OH                               2-methyl-                                                                              t-BuS(R)CH(2-methylpropyl)CH.sub.2 (S-D-Leu)OH                         propyl                                                                         2-butyl t-BuS(R)CH(2-butyl)CH.sub.2 (S-D-Leu)OH                                aminoethyl                                                                             t-BuS(R)CH(aminoethyl)CH.sub.2 (S-D-Leu)OH                             aminobutyl                                                                             t-BuS(R)CH(aminobutyl)CH.sub.2 (S-D-Leu)                               carbamoyl-                                                                             t-BuS(R)CH(carbamoyl-                                                  methyl  methyl)CH.sub.2 (S-D-Leu)OH                                            ______________________________________                                    

10E. Formula 14 Varying R¹ and R³

By following the procedures described in Example 10A and substituting (2S)-2-bromo-4-methylpentanoic acid with other compounds of Formula 2 and (2S)-1-(acetylthio)-2-(t-butylthio)propane with other compounds of Formula 12 (e.g., compounds with R¹ that are prepared according to Examples 9A and 9B) there are obtained the correspondingly substituted compounds of Formula 14 (where R¹ and R³ are as indicated in the table below).

    ______________________________________                                         Formula 14                                                                      ##STR70##                                                                     R.sup.1        R.sup.3                                                         ______________________________________                                         hydrogen       hydrogen                                                        2-propyl       methyl                                                          2-methylpropyl 2-propyl                                                        2-butyl        2-butyl                                                         blocked aminoethyl                                                                            2-methylpropyl                                                  blocked aminobutyl                                                                            blocked 4-hydroxyphenylmethyl                                   carbamoylmethyl                                                                               blocked 3-indolylmethyl                                         hydrogen       4-methoxyphenylmethyl                                           2-propyl       phenylethyl                                                     2-methylpropyl phenylethyl                                                     2-butyl        4-methoxyphenylmethyl                                           blocked aminoethyl                                                                            blocked 3-indolylmethyl                                         blocked aminobutyl                                                                            blocked 4-hydroxyphenylmethyl                                   carbamoylmethyl                                                                               2-methylpropyl                                                  hydrogen       2-butyl                                                         2-propyl       2-propyl                                                        2-methylpropyl methyl                                                          2-butyl        hydrogen                                                        blocked aminoethyl                                                                            hydrogen                                                        blocked aminobutyl                                                                            methyl                                                          carbamoylmethyl                                                                               2-propyl                                                        hydrogen       2-butyl                                                         2-propyl       2-methylpropyl                                                  2-methylpropyl blocked 4-hydroxyphenylmethyl                                   2-butyl        blocked 3-indolylmethyl                                         blocked aminoethyl                                                                            4-methoxyphenylmethyl                                           blocked aminobutyl                                                                            phenylethyl                                                     carbamoylmethyl                                                                               phenylethyl                                                     ______________________________________                                    

EXAMPLE 11 Preparation of t-Bus(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe

11A. Formula 15 Where R¹ Is Methyl, R³ Is 2-Methylpropyl, R⁴ Is Phenylmethyl, R⁵ Is Methyl

To a solution of 98 mg of the t-BuS(S) CHMeCH₂ - (S-D-Leu)-OH and 63 mg of Phe-NHMe in 2 mL of 1,2-dimethoxyethane were added 57 mg of 1-hydroxybenzotriazole and 87 mg of dicyclohexylcarbodiimide with stirring at 0°-5° C. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The solvent was evaporated and the residue was triturated several times with 10% CH₂ Cl₂ in hexane. The filtrate was dried over Na₂ SO₄ and evaporated under vacuum. Purification of the residue by flash chromatography (25% EtOAc in hexane) afforded 150 mg of t-BuS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe as a solid at 97% yield. Characteristic analytical data are as follows: mp 130°-131° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.20-7.34 (m, 5H), 7.12 (d, J=8 Hz, 1H), 6.02 (br s, 1H), 4.62 (q, J= 8 Hz, 1H), 3.31 (t, J=7 Hz, 1H), 3.13 (dd, J=7, 14 Hz, 1H), 3.07 (dd, J=8, 14 Hz, 1H), 2.82 (m, 1H), 2.72 (d, J=5 Hz, 3H), 2.61 (dd, J=6, 13 Hz, 1H), 2.41 (dd, J=8, 13 Hz, 1H), 1.63-1.75 (m, 2H), 1.50 (m, 1H), 1.33 (s, 9H), 1.32 (d, J=5 Hz, 3H), 0.86 (d, J=6 Hz, 3H), 0.88 (d, J=6 Hz, 3H).

11B. Preparation of the Corresponding (2R) Isomer of Formula 15

By following the procedure described in Example 11A and substituting t-BuS(S)CHMeCH₂ --(S-D-Leu)-OH with t-BuS(R)CHMeCH₂ --(S-D-Leu)-OH, 27 mg t-BuS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe was obtained as a solid. Characteristic analytical data are as follows: mp 135°-136° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.20-7.34 (m, 5H), 7.15 (d, J=8 Hz, 1H), 6.05 (br s, 1H), 4.61 (q, J=8 Hz, 1H), 3.30 (dd, J=7, 8 Hz, 1H), 3.14 (dd, J=7, 14 Hz, 1H), 3.07 (dd, J=8, 14 Hz, 1H), 2.75-2.83 (m, 1H), 2.73 (d, J=5 Hz, 3H), 2.58 (dd, J=5, 13 Hz, 1H), 2.34 (dd, J=9, 13 Hz, 1H), 1.63-1.75 (m, 2H), 1.46 (m, 1 H), 1.31 (d, J=7 Hz, 3H), 1.30 (s, 9H), 0.89 (d, J=6 Hz, 3H), 0.88 (d, J=6 Hz, 3H).

11C. Formula 15 Varying R¹

By following the procedures described in Example 11A and substituting t-BuS(S)CHMeCH₂ --(S-D-Leu)-OH with other compounds of Formula 14 there are obtained the correspondingly substituted of compounds of Formula 15 (where R¹, R³, R⁴, R⁵, and R⁶ are as indicated in the table below).

    ______________________________________                                         Formula 15                                                                      ##STR71##                                                                     where R.sup.3 is 2-Methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.1 Name                                                                   ______________________________________                                         hydrogen                                                                               t-BuSCH.sub.2 CH.sub.2 (S-D-Leu)PheNHMe                                2-propyl                                                                               t-BuS(S)CH(2-propyl)CH.sub.2 (S-D-Leu)                                         PheNHMe                                                                2-methyl-                                                                              t-BuS(S)CH(2-methylpropyl)CH.sub.2 (S-D-Leu)                           propyl  PheNHMe                                                                2-butyl t-BuS(S)CH(2-butyl)CH.sub.2 (S-D-Leu)                                          PheNHMe                                                                blocked t-BuS(S)CH(aminoethyl)CH.sub.2 (S-D-Leu)                               aminoethyl                                                                             PheNHMe                                                                blocked t-BuS(S)CH(aminobutyl)CH.sub.2 (S-D-Leu)                               aminobutyl                                                                             PheNHMe                                                                carbamoyl-                                                                             t-BuS(S)CH(carbamoyl-                                                  methyl  methyl)CH.sub.2 (S-D-Leu)PheNHMe                                       ______________________________________                                    

11D. Formula 15 Varying R¹

By following the procedures described in Example 11B and substituting t-BuS(R)CHMeCH₂ --(S-D-Leu)-OH with other compounds of Formula 14 there are obtained the correspondingly substituted compounds of Formula 15 (where R¹, R³, R⁴ R⁵, R⁶ and R⁷ are as indicated in the table below).

    ______________________________________                                         Formula 15                                                                      ##STR72##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.1 Name                                                                   ______________________________________                                         2-propyl                                                                               t-BuS(R)CH(2-propyl)CH.sub.2 (S-D-Leu)                                         PheNHMe                                                                2-methyl-                                                                              t-BuS(R)CH(2-methylpropyl)CH.sub.2 (S-D-Leu)                           propyl  PheNHMe                                                                2-butyl t-BuS(R)CH(2-butyl)CH.sub.2 (S-D-Leu)                                          PheNHMe                                                                blocked t-BuS(R)CH(aminoethyl)CH.sub.2 (S-D-Leu)                               aminoethyl                                                                             PheNHMe                                                                blocked t-BuS(R)CH(aminobutyl)CH.sub.2 (S-D-Leu)                               aminobutyl                                                                             PheNHMe                                                                carbamoyl-                                                                             t-BuS(R)CH(carbamoylmethyl)CH.sub.2 (S-D-Leu)                          methyl  PheNHMe                                                                ______________________________________                                    

11E. Formula 15 Varying R¹, R³, R⁴, R⁵, and R⁶

By following the procedures described in Example 11A and substituting Phe-NHMe with other compounds of Formula 6 and t-BuS(S)CHMeCH₂ --(S-D-Leu)-OH with other compounds of Formula 14 (e.g., compounds with R¹ and R³ that are prepared according to Example 10A) there are obtained the correspondingly substituted compounds of Formula 15 (where R¹, R³, R⁴, R⁵ and R⁶ are as indicated in the tables below).

    ______________________________________                                         Formula 15                                                                      ##STR73##                                                                     where R.sup.5 is methyl or phenylmethyl                                        R.sup.1 R.sup.3        R.sup.4       R.sup.5                                   ______________________________________                                         hydrogen                                                                               hydrogen       phenylethyl   CH.sub.3                                  2-propyl                                                                               methyl         4-methoxyphenyl-                                                                             Bn                                                               methyl                                                  2-methyl-                                                                              2-propyl       blocked 3-    CH.sub.3                                  propyl                 indolylmethyl                                           2-butyl 2-butyl        blocked 4-    Bn                                                               hydroxyphenyl-                                                                 methyl                                                  blocked 2-methylpropyl benzyl        CH.sub.3                                  aminoethyl                                                                     blocked blocked 4-hydroxy-                                                                            blocked 4-    Bn                                        aminobutyl                                                                             phenylmethyl   imidazoylmethyl                                         carbamoyl-                                                                             blocked        blocked 3-    CH.sub.3                                  methyl  3-indolylmethyl                                                                               guanylpropyl                                            hydrogen                                                                               4-methoxyphenyl-                                                                              blocked 4-    Bn                                                methyl         aminobutyl                                              2-propyl                                                                               phenylethyl    2-methylpropyl                                                                               CH.sub.3                                  2-methyl-                                                                              phenylethyl    2-butyl       Bn                                        propyl                                                                         2-butyl 4-methoxyphenyl-                                                                              2-propyl      CH.sub.3                                          methyl                                                                 blocked blocked        methyl        Bn                                        aminoethyl                                                                             3-indolylmethyl                                                        blocked blocked 4-hydroxy-                                                                            hydrogen      CH.sub.3                                  aminobutyl                                                                             phenylmethyl                                                           carbamoyl-                                                                             2-methylpropyl hydrogen      Bn                                        methyl                                                                         hydrogen                                                                               2-butyl        methyl        CH.sub.3                                  2-propyl                                                                               2-propyl       2-propyl      Bn                                        2-methyl-                                                                              methyl         2-butyl       CH.sub.3                                  propyl                                                                         2-butyl hydrogen       2-methylpropyl                                                                               Bn                                        blocked hydrogen       blocked 4-    CH.sub.3                                  aminoethyl             aminobutyl                                              blocked methyl         blocked 3-    Bn                                        aminobutyl             guanylpropyl                                            carbamoyl-                                                                             2-propyl       blocked 4-    CH.sub.3                                  methyl                 imidazoylmethyl                                         hydrogen                                                                               2-butyl        benzyl        Bn                                        2-propyl                                                                               2-methylpropyl blocked 4-    CH.sub.3                                                         hydroxyphenyl-                                                                 methyl                                                  2-methyl-                                                                              blocked 4-hydroxy-                                                                            blocked 3-    Bn                                        ethyl   phenylmethyl   indolylmethyl                                           2-butyl blocked        4-methoxyphenyl-                                                                             CH.sub.3                                          3-indolylmethyl                                                                               methyl                                                  blocked 4-methoxyphenyl-                                                                              phenylethyl   Bn                                        aminoethyl                                                                             methyl                                                                 blocked phenylethyl    phenylethyl   CH.sub.3                                  aminobutyl                                                                     carbamoyl-                                                                             phenylethyl    2-butyl       Bn                                        methyl                                                                         ______________________________________                                    

    ______________________________________                                         Formula 15                                                                      ##STR74##                                                                     where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.1 R.sup.3    R.sup.4      R.sup.6                                        ______________________________________                                         hydrogen                                                                               hydrogen   phenylethyl  hydrogen                                       2-propyl                                                                               methyl     4-methoxy-   2-propyl                                                          phenylmethyl                                                2-methyl-                                                                              2-propyl   blocked 3-   methyl                                         propyl             indolylmethyl                                               2-butyl 2-butyl    blocked 4-   2-butyl                                                           hydroxyphenyl-                                                                 methyl                                                      blocked 2-methyl-  benzyl       2-methylpropyl                                 aminoethyl                                                                             propyl                                                                 blocked blocked    blocked 4-   blocked 4-                                     aminobutyl                                                                             4-hydroxy- imidazoyl-   aminobutyl                                             phenylmethyl                                                                              methyl                                                      carbamoyl-                                                                             blocked 3- blocked 3-   blocked 3-                                     methyl  indolylmethyl                                                                             guanylpropyl guanylpropyl                                   hydrogen                                                                               4-methoxy- blocked 4-   2-imidazoylmethyl                                      phenylmethyl                                                                              aminobutyl                                                  2-propyl                                                                               phenylethyl                                                                               2-methylpropyl                                                                              hydroxymethyl                                  2-methyl-                                                                              phenylethyl                                                                               2-butyl      1-hydroxyethyl                                 propyl                                                                         2-butyl 4-methoxy- 2-propyl     thiolmethyl                                            phenylmethyl                                                           blocked blocked 3- methyl       methylthioethyl                                aminoethyl                                                                             indolylmethyl                                                          blocked blocked    hydrogen     methylthioethyl                                aminobutyl                                                                             4-hydroxy-                                                                     phenylmethyl                                                           carbamoyl-                                                                             2-methyl-  hydrogen     thiolmethyl                                    methyl  propyl                                                                 hydrogen                                                                               2-butyl    methyl       1-hydroxyethyl                                 2-propyl                                                                               2-propyl   2-propyl     hydroxymethyl                                  2-methyl-                                                                              methyl     2-butyl      2-imidazoylmethyl                              propyl                                                                         2-butyl hydrogen   2-methylpropyl                                                                              blocked 3-                                                                     guanylpropyl                                   blocked hydrogen   blocked 4-   blocked 4-                                     aminoethyl         aminobutyl   aminobutyl                                     blocked methyl     blocked 3-   2-methylpropyl                                 aminobutyl         guanylpropyl                                                carbamoyl-                                                                             2-propyl   blocked 4-   2-butyl                                        methyl             imidazoylmethyl                                             hydrogen                                                                               2-butyl    benzyl       methyl                                         2-propyl                                                                               2-methyl-  blocked 4-   2-propyl                                               propyl     hydroxyphenyl-                                                                 methyl                                                      2-methyl-                                                                              blocked    blocked 3-   hydrogen                                       propyl  4-hydroxy- indolylmethyl                                                       phenylmethyl                                                           2-butyl blocked 3- 4-methoxy-   methylthioethyl                                        indolylmethyl                                                                             phenylmethyl                                                blocked 4-methoxy- phenylethyl  thiolmethyl                                    aminoethyl                                                                             phenylmethyl                                                           blocked phenylethyl                                                                               phenylethyl  1-hydroxyethyl                                 aminobutyl                                                                     carbamoyl-                                                                             phenylethyl                                                                               2-butyl      hydrogen                                       methyl                                                                         ______________________________________                                    

EXAMPLE 12 Preparation of 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe

12A. Formula 16 Where R¹ Is Methyl, R³ Is 2-Methylpropyl, R⁴ Is Phenylmethyl, R⁵ Methyl

To a solution of 150 mg of t-BuS(S) CHMeCH₂ - (S-D-Leu)-Phe-NHMe in 1 mL of glacial acetic acid was added 71 mg of 2-NO₂ C₆ H₄ SCl. The mixture was stirred at room temperature for 2 h. The acetic acid was evaporated under vacuum and the residue was purified by flash chromatography (35% EtOAc in hexane) to give 177 mg of 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe at 97% yield. Characteristic analytical data are as follows: mp 138°-140° C.; ¹ H NMR (300 MHz, CDCl₃) δ8.26 (dt, J=2, 8 Hz, 2H), 7.67 (dt, J=l, 8 Hz, 1H), 7.17-7.38 (m, 6H), 6.94 (br d, J=8 Hz, 1H, NH), 5.80 (br s, 1H, NH), 4.55 (q, J=8 Hz, 1H), 3.24 (t, J=7 Hz, 1H), 3.04 (d, J=8 Hz, 2H), 2.93 (m, 1H), 2.73 (d, J=5 Hz, 3H, NMe), 2.63 (dd, J=7, 14 Hz, 1H), 2.41 (dd, J=8, 14 Hz, 1H), 1.59-1.71 (m, 2H), 1.39-1.50 (m, 1H), 1.30 (d, J=7 Hz, 3H), 0.86 (d, J=7 Hz, 3H 0.85 (d, J=7 Hz, 3H).

12B. Preparation of the Corresponding (2R) Isomer of Formula 16

By following the procedure described in Example 12A and substituting the (S)-isomer with t-BuS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe, 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe was obtained at 95% yield. Characteristic analytical data are as follows: mp 170°-172° C.; ¹ H NMR (300 MHz, CDCl₃) δ8.27 (dd, J=1, 3 Hz, 1H), 8.24 (dd, J=l, 3 Hz, 1H), 7.67 (dt, J=l, 7 Hz, 1H), 7.20-7.38 (m, 6H), 6.92 (d, J=7 Hz, 1H), 5.98 (m, 1H), 4.55 (q, J=8 Hz, 1H), 3.15 (t, J=7 Hz, 1H), 3.00-3.12 (m, 2H), 2.80-2.90 (m, 1H), 2.74 (d, J=5 Hz, 3H), 2.55 (dd, J=5, 13 Hz, 1H), 2.27 (dd, J=9, 13 Hz, 1H), 1.52-1.64 (m, 2H), 1.40 (m, 1H), 1.30 (d, J=7 Hz, 3H), 0.84 (d, J=6 Hz, 3H), 0.81 (d, J=6 Hz, 3H).

12C. Formula 16 Varying R¹

By following the procedures described in Example 12A and substituting t-BuS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 15 there are obtained the correspondingly substituted of compounds of Formula 16 (where the R¹, R³, R⁴, R⁵ and R⁶ substituents are as indicated in the table below).

    __________________________________________________________________________     Formula 16                                                                      ##STR75##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.1   Name                                                                 __________________________________________________________________________     hydrogen  2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 CH.sub.2 (SDLeu)PheNHMe        2-propyl  2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-propyl)CH.sub.2 (SDLeu)PheN               HMe                                                                  2-methylpropyl                                                                           2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-methylpropyl)CH.sub.2                     (SDLeu)PheNHMe                                                       2-butyl   2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-butyl)CH.sub.2 (SDLeu)PheNH               Me                                                                   blocked aminoethyl                                                                       2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(aminoethyl)CH.sub.2 (SDLeu)Ph               eNHMe                                                                blocked aminobutyl                                                                       2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(aminobutyl)CH.sub.2 (SDLeu)Ph               eNHMe                                                                carbamoylmethyl                                                                          2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(carbamoylmethyl)CH.sub.2                    (SDLeu)PheNHMe                                                       2-PhtN-ethyl                                                                             2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-PhtN-ethyl)CH.sub.2                       (S(SDLeu)PheNHMe                                                     4-PhtN-butyl                                                                             2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(4-PhtN-butyl)CH.sub.2                       (S(SDLeu)PheNHMe                                                     __________________________________________________________________________

12D. Formula 16 Varying R¹

By following the procedures described in Example 12B and substituting t-BuS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 15 there are obtained the correspondingly substituted of compounds of Formula 16 (where the R¹, R³, R⁴, R⁵, and R⁶ substituents are as indicated in the table below).

    __________________________________________________________________________     Formula 16                                                                      ##STR76##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.1   Name                                                                 __________________________________________________________________________     2-propyl  2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-propyl)CH.sub.2 (SDLeu)PheN               HMe                                                                  2-methylpropyl                                                                           2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-methylpropyl)CH.sub.2                     (SDLeu)PheNHMe                                                       2-butyl   2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-butyl)CH.sub.2 (SDLeu)PheNH               Me                                                                   blocked aminoethyl                                                                       2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(aminoethyl)CH.sub.2 (SDLeu)Ph               eNHMe                                                                blocked aminobutyl                                                                       2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(aminobutyl)CH.sub.2 (SDLeu)Ph               eNHMe                                                                carbamoylmethyl                                                                          2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(carbamoylmethyl)CH.sub.2                    (SDLeu)PheNHMe                                                       2-PhtN-ethyl                                                                             2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-PhtN-ethyl)CH.sub.2                       (SDLeu)heNHMe                                                        2-PhtN-butyl                                                                             2-NO.sub.2 C.sub. 6 H.sub.4 SS(R)CH(4-PhtN-butyl)CH.sub.2                      (SDLeu)PheNHMe                                                       __________________________________________________________________________

12E. Formula 16 Varying R¹, R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 12A and substituting t-BuS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 15 (e.g., compounds that are prepared according to Examples 11A-11E) there are obtained the correspondingly substituted compounds Formula 16 (where the R¹, R³, R⁴, R⁵, and R⁶ substituents are as indicated in the tables below).

    __________________________________________________________________________     Formula 16                                                                      ##STR77##                                                                     where R.sup.5 is methyl or phenylmethyl                                        R.sup.1    R.sup.3      R.sup.4  R.sup.5                                       __________________________________________________________________________     hydrogen   hydrogen     phenylethyl                                                                             CH.sub.3                                      2-propyl   methyl       4-methoxyphenyl-                                                                        Bn                                                                    methyl                                                 2-methylpropyl                                                                            2-propyl     blocked 3-                                                                              CH.sub.3                                                              indolylmethyl                                          2-butyl    2-butyl      blocked 4-                                                                              Bn                                                                    hydroxyphenyl-                                                                 methyl                                                 blocked aminoethyl                                                                        2-methylpropyl                                                                              benzyl   CH.sub.3                                      blocked aminobutyl                                                                        blocked 4-hydroxy-                                                                          blocked 4-                                                                              Bn                                                       phenylmethyl imidazoylmethyl                                        carbamoylmethyl                                                                           blocked 3-indolylmethyl                                                                     blocked 3-                                                                              CH.sub.3                                                              guanylpropyl                                           hydrogen   4-methoxyphenylmethyl                                                                       blocked 4-                                                                              Bn                                                                    aminobutyl                                             2-propyl   phenylethyl  2-methylpropyl                                                                          CH.sub.3                                      2-methylpropyl                                                                            phenylethyl  2-butyl  Bn                                            2-butyl    4-methoxyphenylmethyl                                                                       2-propyl CH.sub.3                                      blocked aminoethyl                                                                        blocked 3-indolylmethyl                                                                     methyl   Bn                                            blocked aminobutyl                                                                        blocked 4-hydroxy-                                                                          hydrogen CH.sub.3                                                 phenylmethyl                                                        carbamoylmethyl                                                                           2-methylpropyl                                                                              hydrogen Bn                                            hydrogen   2-butyl      methyl   CH.sub.3                                      2-propyl   2-propyl     2-propyl Bn                                            2-methylpropyl                                                                            methyl       2-butyl  CH.sub.3                                      2-butyl    hydrogen     2-methylpropyl                                                                          Bn                                            blocked aminoethyl                                                                        hydrogen     blocked 4-                                                                              CH.sub.3                                                              aminobutyl                                             blocked aminobutyl                                                                        methyl       blocked 3-                                                                              Bn                                                                    guanylpropyl                                           carbamoylmethyl                                                                           2-propyl     blocked 4-                                                                              CH.sub.3                                                              imidazoylmethyl                                        hydrogen   2-butyl      benzyl   Bn                                            2-propyl   2-methylpropyl                                                                              blocked 4-                                                                              CH.sub.3                                                              hydroxyphenyl-                                                                 methyl                                                 2-methylpropyl                                                                            blocked 4-hydroxy-                                                                          blocked 3-                                                                              Bn                                                       phenylmethyl indolylmethyl                                          2-butyl    blocked 3-indolylmethyl                                                                     4-methoxyphenyl-                                                                        CH.sub.3                                                              methyl                                                 blocked aminoethyl                                                                        4-methoxyphenylmethyl                                                                       phenylethyl                                                                             Bn                                            blocked aminobutyl                                                                        phenylethyl  phenylethyl                                                                             CH.sub.3                                      carbamoylmethyl                                                                           phenylethyl  2-butyl  Bn                                            __________________________________________________________________________

    __________________________________________________________________________     Formula 16                                                                      ##STR78##                                                                     where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.1  R.sup.3   R.sup.4  R.sup.6                                            __________________________________________________________________________     hydrogen hydrogen  phenylethyl                                                                             hydrogen                                           2-propyl methyl    4-methoxy-                                                                              2-propyl                                                              phenylmethyl                                                2-methylpropyl                                                                          2-propyl  blocked 3-                                                                              methyl                                                                indolylmethyl                                               2-butyl  2-butyl   blocked 4-                                                                              2-butyl                                                               hydroxyphenyl-                                                                 methyl                                                      blocked  2-methylpropyl                                                                           benzyl   2-methylpropyl                                     aminoethyl                                                                     blocked  blocked 4-hydroxy-                                                                       blocked 4-                                                                              blocked 4-                                         aminobutyl                                                                              phenylmethyl                                                                             imidazoyl-                                                                              aminobutyl                                                            methyl                                                      carbamoylmethyl                                                                         blocked 3-indolyl-                                                                       blocked 3-                                                                              blocked 3-                                                  methyl    guanylpropyl                                                                            guanylpropyl                                       hydrogen 4-methoxyphenyl-                                                                         blocked 4-                                                                              2-imidazoylmethyl                                           methyl    aminobutyl                                                  2-propyl phenylethyl                                                                              2-methylpropyl                                                                          hydroxymethyl                                      2-methylpropyl                                                                          phenylethyl                                                                              2-butyl  1-hydroxyethyl                                     2-butyl  4-methoxyphenyl-                                                                         2-propyl thiolmethyl                                                 methyl                                                                blocked  blocked 3-indolyl-                                                                       methyl   methylthioethyl                                    aminoethyl                                                                              methyl                                                                blocked  blocked 4-hydroxy-                                                                       hydrogen methylthioethyl                                    aminobutyl                                                                              phenylmethyl                                                          carbamoylmethyl                                                                         2-methylpropyl                                                                           hydrogen thiolmethyl                                        hydrogen 2-butyl   methyl   1-hydroxyethyl                                     2-propyl 2-propyl  2-propyl hydroxymethyl                                      2-methylpropyl                                                                          methyl    2-butyl  2-imidazoylmethyl                                  2-butyl  hydrogen  2-methylpropyl                                                                          blocked 3-                                                                     guanylpropyl                                       blocked  hydrogen  blocked 4-                                                                              blocked 4-                                         aminoethyl         aminobutyl                                                                              aminobutyl                                         blocked  methyl    blocked 3-                                                                              2-methylpropyl                                     aminobutyl         guanylpropyl                                                carbamoylmethyl                                                                         2-propyl  blocked 4-                                                                              2-butyl                                                               imidazoyl-                                                                     methyl                                                      hydrogen 2-butyl   benzyl   methyl                                             2-propyl 2-methylpropyl                                                                           blocked 4-                                                                              2-propyl                                                              hydroxyphenyl-                                                                 methyl                                                      2-methylpropyl                                                                          blocked 4-hydroxy-                                                                       blocked 3-                                                                              hydrogen                                                    phenylmethyl                                                                             indolylmethyl                                               2-butyl  blocked 3-indolyl-                                                                       4-methoxy-                                                                              methylthioethyl                                             methyl    phenylmethyl                                                blocked  4-methoxyphenyl-                                                                         phenylethyl                                                                             thiolmethyl                                        aminoethyl                                                                              methyl                                                                blocked  phenylethyl                                                                              phenylethyl                                                                             1-hydroxyethyl                                     aminobutyl                                                                     carbamoylmethyl                                                                         phenylethyl                                                                              2-butyl  hydrogen                                           __________________________________________________________________________

EXAMPLE 13 Preparation of HS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe

13A. Formula I Where R¹ Is Methyl, R³ Is 2-Methylpropyl R⁴ Is Phenylmethyl, R⁵ Is Methyl

To a solution of 167 mg of 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe in 2 mL of MeOH and 0.5 mL of dioxane were added 0.5 mL of 2-mercaptoethanol and 0.78 mL of 0.4M NaOH solution. The mixture was stirred at room temperature under nitrogen for 30 min. The reaction mixture was then poured into water, acidified with acetic acid and extracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum. Purification of the residue by flash chromatography (25% EtOAc in hexane) afforded 89 mg of HS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe as a solid at 74% yield. Characteristic analytical data are as follows: mp 157°-158° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.20-7.35 (m, 5H), 6.98 (br d, J=8 Hz, 1H, NH), 5.85 (br s, 1H, NH), 4.60 (q, J=8 Hz, 1H), 3.27 (dd, J=7, 8 Hz, 1H), 3.15 (dd, J=7, 14 Hz, 1H), 3.07 (dd, J=8, 14 Hz, 1H), 2.91-3.03 (m, 1H), 2.75 (d, J=5 Hz, 3H, NMe), 2.41 (dd, J=6, 13 Hz, 1H), 2.35 (dd, J=8, 13 Hz, 1H), 1.88 (d, J=6 Hz, 1H, SH), 1.62-1.72 (m, 2H), 1.50 (m, 1H), 1.28 (d, J=7 Hz, 3H), 0.90 (d, J=6 Hz, 3H), 0.89 (d, J=6 Hz, 3H); ¹³ C NMR (75 MHz, CDCl₃) δ172.92, 171.54, 136.96, 129.35, 128.96, 127.27, 54.52, 48.36 (CH), 42.0 (CH₂), 41.24 (CH₂), 37.78 (CH), 34.85, 26.01 (CH), 25.87 (CH), 23.64 (CH₃), 22.32 (CH₃), 21.73 (CH₃); [α]_(D) ²⁵ +47° (c=0.40, MeOH). Anal. Calcd for C₁₉ H₃₀ N₂ O₂ S₂ : C, 59.65; H, 7.90; N, 7.32; S, 16.76. Found: C, 59.72; H, 7.96; N, 7.37; S, 16.83.

13B. Preparation of the Corresponding (2R) Isomer of Formula I

By following the procedure described in Example 13A and substituting the (S)-isomer with 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe gave HS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe as a solid at 70% yield. Characteristic analytical data are as follows: mp 155°-157° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.20-7.34 (m, 5H), 7.07 (d, J=8 Hz, 1H), 6.04 (br s, 1H), 4.64 (q, J=8 Hz, 1H), 3.30 (dd, J=7, 8 Hz, 1H), 3.15 (dd, J=7, 14 Hz, 1H), 3.07 (dd, J=8, 14 Hz, 1H), 2.96 (m, 1H), 2.75 (d, J=5 Hz, 3H), 2.42 (d, J=7 Hz, 2H), 1.78 (d, J=6 Hz, 1H, SH), 1.60-1.72 (m, 2H), 1.46 (m, 1H), 1.31 (d, J=7 Hz, 3H), 0.89 (d, J=6 Hz, 3H), 0.88 (d, J=6 Hz, 3H).

13C. Formula I Varying R¹

By following the procedures described in Example 13A and substituting 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 16 there are obtained the correspondingly substituted of compounds of Formula I (where the R¹, R³, R⁴, R⁵, and R⁶ substituents are as indicated in the table below).

    __________________________________________________________________________     Formula I                                                                       ##STR79##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.1  Name                                                                  __________________________________________________________________________     hydrogen HSCH.sub.2 CH.sub.2 (SDLeu)PheNHMe                                    2-propyl HS(S)CH(2-propyl)CH.sub.2 (SDLeu)PheNHMe                              2-methylpropyl                                                                          HS(S)CH(2-methylpropyl)CH.sub.2 (SDLeu)PheNHMe                        2-butyl  HS(S)CH(2-butyl)CH.sub.2 (SDLeu)PheNHMe                               2-aminoethyl                                                                            HS(S)CH(2-aminoethyl)CH.sub.2 (SDLeu)PheNHMe                          2-aminobutyl                                                                            HS(S)CH(4-aminobutyl)CH.sub.2 (SDLeu)PheNHMe                          carbamoylmethyl                                                                         HS(S)CH(carbamoylmethyl)CH.sub.2 (SDLeu)PheNHMe                       2-PhtN-ethyl                                                                            HS(S)CH(2-PhtN-ethyl)CH.sub.2 (SDLeu)PheNHMe                          2-PhtN-butyl                                                                            HS(S)CH(4-PhtN-butyl)CH.sub.2 (SDLeu)PheNHMe                          __________________________________________________________________________

13D. Formula I Varying R¹

By following the procedures described in Example 13B and substituting 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 16 there are obtained the correspondingly substituted compounds of Formula I (where the R¹, R³, R⁴, R⁵ and R⁶ substituents are as indicated in the table below).

    __________________________________________________________________________     Formula I                                                                       ##STR80##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.1  Name                                                                  __________________________________________________________________________     2-propyl HS(R)CH(2-propyl)CH.sub.2 (S(SDLeu)PheNHMe                            2-methylpropyl                                                                          HS(R)CH(2-methylpropyl)CH.sub.2 (SDLeu)PheNHMe                        2-butyl  HS(R)CH(2-butyl)CH.sub.2 (SDLeu)PheNHMe                               aminoethyl                                                                              HS(R)CH(aminoethyl)CH.sub.2 (SDLeu)PheNHMe                            aminobutyl                                                                              HS(R)CH(aminobutyl)CH.sub.2 (SDLeu)PheNHMe                            carbamoylmethyl                                                                         HS(R)CH(carbamoylmethyl)CH.sub.2 (SDLeu)PheNHMe                       carbamoylpentyl                                                                         HS(R)CH(carbamoylpentyl)CH.sub.2 (SDLeu)PheNHMe                       2-PhtN-ethyl                                                                            HS(R)CH(2-PhtN-ethyl)CH.sub.2 (SDLeu)PheNHMe                          4-PhtN-butyl                                                                            HS(R)CH(4-PhtN-butyl)CH.sub.2 (SDLeu)PheNHMe                          __________________________________________________________________________

13E. Formula I Varying R¹, R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 13A and substituting 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe with other compounds of Formula 16 (e.g., compounds that are prepared according to Examples 12A-12E) there are obtained the correspondingly substituted compounds of Formula I (where the R¹, R³, R⁴, R⁵ and R⁶ substituents are as indicated in the tables below).

    ______________________________________                                         Formula I                                                                       ##STR81##                                                                     where R.sup.5 is methyl or phenylmethyl                                        R.sup.1    R.sup.3      R.sup.4      R.sup.5                                   ______________________________________                                         hydrogen   hydrogen     phenylethyl  CH.sub.3                                  2-propyl   methyl       4-methoxyphenyl-                                                                            Bn                                                                methyl                                                 2-methylpropyl                                                                            2-propyl     3-indolylmethyl                                                                             CH.sub.3                                  2-butyl    2-butyl      4-hydroxyphenyl-                                                                            Bn                                                                methyl                                                 aminoethyl 2-methylpropyl                                                                              benzyl       CH.sub.3                                  aminobutyl 4-hydroxyphenyl-                                                                            4-imidazoylmethyl                                                                           Bn                                                   methyl                                                              carbamoylmethyl                                                                           3-indolylmethyl                                                                             3-guanylpropyl                                                                              CH.sub.3                                  hydrogen   4-methoxyphenyl-                                                                            4-aminobutyl Bn                                                   methyl                                                              2-propyl   phenylethyl  2-methylpropyl                                                                              CH.sub.3                                  2-methylpropyl                                                                            phenylethyl  2-butyl      Bn                                        2-butyl    4-methoxyphenyl-                                                                            2-propyl     CH.sub.3                                             methyl                                                              aminoethyl 3-indolylmethyl                                                                             methyl       Bn                                        aminobutyl 4-hydroxyphenyl-                                                                            hydrogen     CH.sub.3                                             methyl                                                              carbamoylmethyl                                                                           2-methylpropyl                                                                              hydrogen     Bn                                        hydrogen   2-butyl      methyl       CH.sub.3                                  2-propyl   2-propyl     2-propyl     Bn                                        2-methylpropyl                                                                            methyl       2-butyl      CH.sub.3                                  2-butyl    hydrogen     2-methylpropyl                                                                              Bn                                        aminoethyl hydrogen     4-aminobutyl CH.sub.3                                  aminobutyl methyl       3-guanylpropyl                                                                              Bn                                        carbamoylmethyl                                                                           2-propyl     4-imidazoylmethyl                                                                           CH.sub.3                                  hydrogen   2-butyl      benzyl       Bn                                        2-propyl   2-methylpropyl                                                                              4-hydroxyphenyl-                                                                            CH.sub.3                                                          methyl                                                 2-methylpropyl                                                                            4-hydroxyphenyl-                                                                            3-indolylmethyl                                                                             Bn                                                   methyl                                                              2-butyl    3-indolylmethyl                                                                             4-methoxyphenyl-                                                                            CH.sub.3                                                          methyl                                                 aminoethyl 4-methoxyphenyl-                                                                            phenylethyl  Bn                                                   methyl                                                              aminobutyl phenylethyl  phenylethyl  CH.sub.3                                  carbamoylmethyl                                                                           phenylethyl  2-butyl      Bn                                        ______________________________________                                    

    __________________________________________________________________________     Formula I                                                                       ##STR82##                                                                     where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.1  R.sup.3   R.sup.4 R.sup.6                                             __________________________________________________________________________     hydrogen hydrogen  phenylethyl                                                                            hydrogen                                            2-propyl methyl    4-methoxy-                                                                             2-propyl                                                               phenylmethyl                                                2-methylpropyl                                                                          2-propyl  3-indolyl-                                                                             methyl                                                                 methyl                                                      2-butyl  2-butyl   4-hydroxy-                                                                             2-butyl                                                                phenylmethyl                                                aminoethyl                                                                              2-methylpropyl                                                                           benzyl  2-methylpropyl                                      aminobutyl                                                                              4-hydroxy-                                                                               4-imidazoyl-                                                                           4-aminobutyl                                                 phenylmethyl                                                                             methyl                                                      carbamoylmethyl                                                                         3-indolylmethyl                                                                          3-guanylpropyl                                                                         3-guanylpropyl                                      hydrogen 4-methoxyphenyl-                                                                         4-aminobutyl                                                                           2-imidazoylmethyl                                            methyl                                                                2-propyl phenylethyl                                                                              2-methylpropyl                                                                         hydroxymethyl                                       2-methylpropyl                                                                          phenylethyl                                                                              2-butyl 1-hydroxyethyl                                      2-butyl  4-methoxyphenyl-                                                                         2-propyl                                                                               thiolmethyl                                                  methyl                                                                aminoethyl                                                                              3-indolylmethyl                                                                          methyl  methylthioethyl                                     aminobutyl                                                                              4-hydroxy-                                                                               hydrogen                                                                               methylthioethyl                                              phenylmethyl                                                          carbamoylmethyl                                                                         2-methylpropyl                                                                           hydrogen                                                                               thiolmethyl                                         hydrogen 2-butyl   methyl  1-hydroxyethyl                                      2-propyl 2-propyl  2-propyl                                                                               hydroxymethyl                                       2-methylpropyl                                                                          methyl    2-butyl 2-imidazoylmethyl                                   2-butyl  hydrogen  2-methylpropyl                                                                         3-guanylpropyl                                      aminoethyl                                                                              hydrogen  blocked 4-                                                                             4-aminobutyl                                                           aminobutyl                                                  aminobutyl                                                                              methyl    3-guanylpropyl                                                                         2-methylpropyl                                      carbamoylmethyl                                                                         2-propyl  4-imidazoyl-                                                                           2-butyl                                                                methyl                                                      hydrogen 2-butyl   benzyl  methyl                                              2-propyl 2-methylpropyl                                                                           4-hydroxy-                                                                             2-propyl                                                               phenylmethyl                                                2-methylpropyl                                                                          4-hydroxy-                                                                               3-indolyl-                                                                             hydrogen                                                     phenylmethyl                                                                             methyl                                                      2-butyl  3-indolylmethyl                                                                          4-methoxy-                                                                             methylthioethyl                                                        phenylmethyl                                                aminoethyl                                                                              4-methoxyphenyl-                                                                         phenylethyl                                                                            thiolmethyl                                                  methyl                                                                aminobutyl                                                                              phenylethyl                                                                              phenylethyl                                                                            1-hydroxyethyl                                      carbamoylmethyl                                                                         phenylethyl                                                                              2-butyl hydrogen                                            __________________________________________________________________________

EXAMPLE 14 Preparation of t-BuS(R)CHMeCH₂ SCH₂ NPht

14A. Formula 18 Where R² Is Methyl

To a solution of 83 mg of Na in 3 mL of EtOH was added 671 mg of t-BuS(R)CHMeCH₂ SAc in 2 mL of EtOH. The mixture was stirred at room temperature for 15 min under nitrogen, poured into water, acidified with acetic acid and extracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum to give 480 mg of t-BuS(R)CHMeCH₂ SH (i.e., Formula 17 where R² is methyl) at 90% yield. To a solution of the crude mercaptan in 8 mL of CH₂ Cl₂ was added 0.78 mL of diisopropylethylamine and 843 mg of N-(bromomethyl)phthalimide with stirring at room temperature under nitrogen. Stirring was continued at room temperature for 18 h. The mixture was diluted with 75 mL of CH₂ Cl₂ and extracted with 1M HCl. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum. The residue was purified by flash chromatography (10% EtOAc in hexane) to give 846 mg of t-BuS(R)CHMeCH₂ SCH₂ NPht as a solid at 81% yield. Characteristic analytical data are as follows: mp 63°-64° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.88 (d, J=5 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 4.81 (dd, J=14, 17 Hz, 2H), 3.11 (dd, J=5, 12 Hz, 1H), 2.93 (m, 1H), 2.84 (dd, J=8, 12 Hz, 1H), 1.37 (d, J=7 Hz, 3H), 1.32 (s, 9H).

14B. Preparation of the Corresponding (S) Isomer of Formula 18

By following the procedure described in Example 14A and substituting the (R)-isomer with t-BuS(S)CHMeCH₂ SAc there is obtained t-BuS(S)CHMeCH₂ SCH₂ NPht.

14C. Formula 18 Varying R²

By following the procedures described in Example 14A and substituting t-BuS(R)CHMeCH₂ SAc with other compounds of Formula 12A there are obtained the correspondingly substituted of compounds of Formula 18 (where R² is as indicated in the table below).

    ______________________________________                                         Formula 18                                                                      ##STR83##                                                                     R.sup.2    Name                                                                ______________________________________                                         hydrogen   t-BuSCH.sub.2 CH.sub.2 SCH.sub.2 NPht                               2-propyl   t-BuS(R)CH(2-propyl)CH.sub.2 SCH.sub.2 NPht                         2-methylpropyl                                                                            t-BuS(R)CH(2-methylpropyl)CH.sub.2 SCH.sub.2 NPht                   2-butyl    t-BuS(R)CH(2-butyl)CH.sub.2 SCH.sub.2 NPht                          blocked    t-BuS(R)CH(aminoethyl)CH.sub.2 SCH.sub.2 NPht                       aminoethyl                                                                     blocked    t-BuS(R)CH(aminobutyl)CH.sub.2 SCH.sub.2 NPht                       aminobutyl                                                                     carbamoylmethyl                                                                           t-BuS(R)CH(carbamoylmethyl)CH.sub.2 SCH.sub.2 NPht                  ______________________________________                                    

14D. Formula 18 Varying R²

By following the procedures described in Example 14B and substituting t-BuS(S)CHMeCH₂ SAc with other compounds of Formula 12A there are obtained the correspondingly substituted compounds of Formula 18 (where R² is as indicated in the table below).

    ______________________________________                                         Formula 18                                                                      ##STR84##                                                                     R.sup.2    Name                                                                ______________________________________                                         2-propyl   t-BuS(S)CH(2-propyl)CH.sub.2 SCH.sub.2 NPht                         2-methylpropyl                                                                            t-BuS(S)CH(2-methylpropyl)CH.sub.2 SCH.sub.2 NPht                   2-butyl    t-BuS(S)CH(2-butyl)CH.sub.2 SCH.sub.2 NPht                          blocked    t-BuS(S)CH(aminoethyl)CH.sub.2 SCH.sub.2 NPht                       aminoethyl                                                                     blocked    t-BuS(S)CH(aminobutyl)CH.sub.2 SCH.sub.2 NPht                       aminobutyl                                                                     carbamoylmethyl                                                                           t-BuS(S)CH(carbamoylmethyl)CH.sub.2 SCH.sub.2 NPht                  ______________________________________                                    

EXAMPLE 15 Preparation of 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ SCH₂ NPht

15A. Formula 19 Where R² Is Methyl

To a solution of 423 mg of t-BuS(R)CHMeCH₂ SCH₂ NPht in 3.5 mL of acetic acid was added 250 mg of 2-nitrobenzenesulfenyl chloride. The mixture was stirred at room temperature for 2 h. The acetic acid was evaporated under vacuum and the residue was purified by flash chromatography (10% EtOAc in hexane) to give 500 mg of 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ SCH₂ NPht as a gum at 92% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ8.34 (d, J=8 Hz, 1H), 8.24 (d, J=8 Hz, 1H), 7.88 (d, J=5 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.66 (t, J=7 Hz, 1H), 7.31 (t, J=7 Hz, 1H), 4.68 (dd, J=14, 19 Hz, 2H), 3.12 (m, 2H), 2.78 (dd, J=7, 13 Hz, 1H), 1.41 (d, J=7 Hz, 3H).

15B. Preparation of the Corresponding (S) Isomer Of Formula 19

By following the procedure described in Example 15A and substituting the (R)-isomer with t-BuS(S)CHMeCH₂ SCH₂ NPht there is obtained 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ SCH₂ NPht.

15C. Formula 19 Varying R²

By following the procedures described in Example 15A and substituting t-BuS(R)CHMeCH₂ SCH₂ NPht with other compounds of Formula 18 there are obtained the correspondingly substituted compounds of Formula 19 (where R² is as indicated in the table below).

    __________________________________________________________________________     Formula 19                                                                      ##STR85##                                                                     R.sup.2   Name                                                                 __________________________________________________________________________     hydrogen  2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 CH.sub.2 SCH.sub.2 NPht        2-propyl  2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-propyl)CH.sub.2 SCH.sub.2                 NPht                                                                 2-methylpropyl                                                                           2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-methylpropyl)CH.sub.2                     SCH.sub.2 NPht                                                       2-butyl   2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(2-butyl)CH.sub.2 SCH.sub.2                  NPht                                                                 blocked   2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(aminoethyl)CH.sub.2 SCH.sub.2                NPht                                                                aminoethyl                                                                     blocked   2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(aminobutyl)CH.sub.2 SCH.sub.2                NPht                                                                aminobutyl                                                                     carbamoylmethyl                                                                          2-NO.sub.2 C.sub.6 H.sub.4 SS(R)CH(carbamoylmethyl)CH.sub.2                    SCH.sub.2 NPht                                                       __________________________________________________________________________

15D. Formula 19 Varying R²

By following the procedures described in Example 15B and substituting t-BuS(S)CHMeCH₂ SCH₂ NPht with other compounds of Formula 18 there are obtained the correspondingly substituted compounds of Formula 19 (where R² is as indicated in the table below).

    __________________________________________________________________________     Formula 19                                                                      ##STR86##                                                                     R.sup.2   Name                                                                 __________________________________________________________________________     2-propyl  2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-propyl)CH.sub.2 SCH.sub.2                 NPht                                                                 2-methylpropyl                                                                           2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-methylpropyl)CH.sub.2                     SCH.sub.2 NPht                                                       2-butyl   2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(2-butyl)CH.sub.2 SCH.sub.2                  NPht                                                                 blocked   2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(aminoethyl)CH.sub.2 SCH.sub.2                NPht                                                                aminoethyl                                                                     blocked   2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(aminobutyl)CH.sub.2 SCH.sub.2                NPht                                                                aminobutyl                                                                     carbamoylmethyl                                                                          2-NO.sub.2 C.sub.6 H.sub.4 SS(S)CH(carbamoylmethyl)CH.sub.2                    SCH.sub.2 NPht                                                       __________________________________________________________________________

EXAMPLE 16 Preparation of PhtNCH₂ SCH₂ (R)CHMeSH

16A. Formula 20 Where R² Is Methyl

To a solution of 500 mg of 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ SCH₂ NPht in 3 mL of MeOH and 1.5 mL of dioxane was added 1.65 mL of 2-mercaptoethanol and 2.94 mL of 0.4M NaOH. The mixture was stirred at room temperature under nitrogen for 30 min. The reaction mixture was poured into water, acidified with acetic acid and extracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum. The residue was purified by flash chromatography (35% CH₂ Cl₂ in hexane) to give 147 mg of HS(R)CHMeCH₂ SCH₂ NPht as a gum at 46% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ7.88 (d, J=5 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 4.80 (s, 2H), 3.20 (2dd, J=5, 9 Hz, 1H), 2.94 (d, J=7 Hz, 2H), 1.93 (d, J=6 Hz, 1H, SH), 1.39 (d, J=7 Hz, 3H).

16B. Preparation of the Corresponding (S) Isomer of Formula 20

By following the procedure described in Example 16A and substituting the (R)-isomer with 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ SCH₂ NPht there is obtained HS(S)CHMeCH₂ SCH₂ NPht.

16C. Formula 20 Varying R²

By following the procedures described in Example 16A and substituting 2-NO₂ C₆ H₄ SS(R)CHMeCH₂ SCH₂ NPht with other compounds of Formula 19 there are obtained the correspondingly substituted compounds of Formula 20 (where R² is as indicated in the table below).

    ______________________________________                                         Formula 20                                                                      ##STR87##                                                                     R.sup.2    Name                                                                ______________________________________                                         hydrogen   HSCH.sub.2 CH.sub.2 SCH.sub.2 NPht                                  2-propyl   HS(R)CH(2-propyl)CH.sub.2 SCH.sub.2 NPht                            2-methylpropyl                                                                            HS(R)CH(2-methylpropyl)CH.sub.2 SCH.sub.2 NPht                      2-butyl    HS(R)CH(2-butyl)CH.sub.2 SCH.sub.2 NPht                             blocked    HS(R)CH(aminoethyl)CH.sub.2 SCH.sub.2 NPht                          aminoethyl                                                                     blocked    HS(R)CH(aminobutyl)CH.sub.2 SCH.sub.2 NPht                          aminobutyl                                                                     carbamoylmethyl                                                                           HS(R)CH(carbamoylmethyl)CH.sub.2 SCH.sub.2 NPht                     ______________________________________                                    

16D. Formula 20 Varying R²

By following the procedures described in Example 16B and substituting 2-NO₂ C₆ H₄ SS(S)CHMeCH₂ SCH₂ NPht with other compounds of Formula 19 there are obtained the correspondingly substituted compounds of Formula 20 (where R² is as indicated in the table below).

    ______________________________________                                         Formula 20                                                                      ##STR88##                                                                     R.sup.2    Name                                                                ______________________________________                                         2-propyl   HS(S)CH(2-propyl)CH.sub.2 SCH.sub.2 NPht                            2-methylpropyl                                                                            HS(S)CH(2-methylpropyl)CH.sub.2 SCH.sub.2 NPht                      2-butyl    HS(S)CH(2-butyl)CH.sub.2 SCH.sub.2 NPht                             blocked    HS(S)CH(aminoethyl)CH.sub.2 SCH.sub.2 NPht                          aminoethyl                                                                     blocked    HS(S)CH(aminobutyl)CH.sub.2 SCH.sub.2 NPht                          aminobutyl                                                                     carbamoylmethyl                                                                           HS(S)CH(carbamoylmethyl)CH.sub.2 SCH.sub.2 NPht                     ______________________________________                                    

EXAMPLE 17 Preparation of PhtNCH₂ SCH₂ (R)CHMe--(S-D-Leu)-O t-Butyl Ester

17A. Formula 22 Where R² Is Methyl and R⁵ Is 2-Methylpropyl

To a solution of 147 mg of PhtNCH₂ SCH₂ (R)CHMeSH and 152 mg of (2S)-2-bromo-4-methylpentanoic acid tert-butyl ester in 0.4 mL of acetonitrile was added 0.2 mL of N,N-diisopropylethylamine. The mixture was stirred at room temperature under nitrogen for 2 days. The solvent was removed under vacuum, the residue dissolved in CH₂ Cl₂ and washed extracted with 1M HCl. The organic layer was dried over Na₂ SO₄, evaporated under vacuum, and the residue was purified by flash chromatography (5% EtOAc in hexane) to give 172 mg of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-O t-Bu at 72% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ7.88 (d, J=5 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 4.81 (s, 2H), 3.43 (dd, J=6, 9 Hz, 1H), 3.17 (m, 2H), 2.82 (m, 1H), 1.71 (m, 2H), 1.46 (s, 9H), 1.40 (m, 1H), 1.37 (d, J=7 Hz, 3H), 0.94 (d, J=7 Hz, 3H), 0.92 (d, J=7 Hz, 3H).

17B. Preparation of the Corresponding (S) Isomer of Formula 22

By following the procedure described in Example 17A and substituting the (R)-isomer with PhtNCH₂ SCH₂ (S)CHMeSH there is obtained PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-O t-Bu.

17C. Formula 22 Varying R²

By following the procedures described in Example 17A and substituting PhtNCH₂ SCH₂ (R)CHMeSH with other compounds of Formula 20 there are obtained the correspondingly substituted compounds of Formula 22 (where R² is as indicated in the table below).

    __________________________________________________________________________     Formula 22                                                                      ##STR89##                                                                     where R.sup.3 is 2-methylpropyl                                                R.sup.2   Name                                                                 __________________________________________________________________________     hydrogen  PhtNCH.sub.2 SCH.sub.2 CH.sub.2 (SDLeu)O(t-Bu)                       2-propyl  PhtNCH.sub.2 SCH.sub.2 (R)CH(2-propyl)-(SDLeu)O(t-Bu)                2-methylpropyl                                                                           PhtNCH.sub.2 SCH.sub.2 (R)CH(2-methylpropyl)-(SDLeu)O(t-Bu)          2-butyl   PhtNCH.sub.2 SCH.sub.2 (R)CH(2-butyl)-(SDLeu)O(t-Bu)                 blocked aminoethyl                                                                       PhtNCH.sub.2 SCH.sub.2 (R)CH(aminoethyl)-(SDLeu)O(t-Bu)              blocked aminobutyl                                                                       PhtNCH.sub.2 SCH.sub.2 (R)CH(aminobutyl)-(SDLeu)O(t-Bu)              carbamoylmethyl                                                                          PhtNCH.sub.2 SCH.sub.2 (R)CH(carbamoylmethyl)-(SDLeu)O(t-Bu)         __________________________________________________________________________

17D. Formula 22 Varying R²

By following the procedures described in Example 17B and substituting PhtNCH₂ SCH₂ (S)CHMeSH with other compounds of Formula 20 there are obtained the correspondingly substituted compounds of Formula 22 (where R² and R³ are as indicated in the table below).

    __________________________________________________________________________     Formula 22                                                                      ##STR90##                                                                     where R.sup.3 is 2-methylpropyl                                                R.sup.2   Name                                                                 __________________________________________________________________________     2-propyl  PhtNCH.sub.2 SCH.sub.2 (S)CH(2-propyl)-(SDLeu)O(t-Bu)                2-methylpropyl                                                                           PhtNCH.sub.2 SCH.sub.2 (S)CH(2-methylpropyl)-(SDLeu)O(t-Bu)          2-butyl   PhtNCH.sub.2 SCH.sub.2 (S)CH(2-butyl)-(SDLeu)O(t-Bu)                 blocked aminoethyl                                                                       PhtNCH.sub.2 SCH.sub.2 (S)CH(aminoethyl)-(SDLeu)O(t-Bu)              blocked aminobutyl                                                                       PhtNCH.sub.2 SCH.sub.2 (S)CH(aminobutyl)-(SDLeu)O(t-Bu)              carbamoylmethyl                                                                          PhtNCH.sub.2 SCH.sub.2 (S)CH(carbamoylmethyl)-(SDLeu)O(t-Bu)         __________________________________________________________________________

17E. Formula 22 Varying R² and R³

By following the procedures described in Example 17A and substituting (2S)-2-bromo-4-methylpentanoic acid tert-butyl ester with other compounds of Formula 21 (where R³ is hydrogen, lower alkyl, aralkyl or heteroaralkyl) and PhtNCH₂ SCH₂ (R)CHMeSH with other compounds of Formula 20 (e.g., compounds with R² that are prepared according to Example 16A and further exemplified in Example 16B) there are obtained the correspondingly substituted compounds of Formula 22 (where n, R² and R³ are as indicated in the table below).

    ______________________________________                                         Formula 22                                                                      ##STR91##                                                                     R.sup.2        R.sup.3                                                         ______________________________________                                         hydrogen       hydrogen                                                        2-propyl       methyl                                                          2-methylpropyl 2-propyl                                                        2-butyl        2-butyl                                                         blocked aminoethyl                                                                            2-methylpropyl                                                  blocked aminobutyl                                                                            blocked 4-hydroxyphenylmethyl                                   carbamoylmethyl                                                                               blocked 3-indolylmethyl                                         hydrogen       4-methoxyphenylmethyl                                           2-propyl       phenylethyl                                                     2-methylpropyl phenylethyl                                                     2-butyl        4-methoxyphenylmethyl                                           blocked aminoethyl                                                                            blocked 3-indolylmethyl                                         blocked aminobutyl                                                                            blocked 4-hydroxyphenylmethyl                                   carbamoylmethyl                                                                               2-methylpropyl                                                  hydrogen       2-butyl                                                         2-propyl       2-propyl                                                        2-methylpropyl methyl                                                          2-butyl        hydrogen                                                        blocked aminoethyl                                                                            hydrogen                                                        blocked aminobutyl                                                                            methyl                                                          carbamoylmethyl                                                                               2-propyl                                                        ______________________________________                                    

EXAMPLE 18 Preparation of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-OH

18A. Formula 23 Where R² Is Methyl and R³ Is 2-Methylpropyl

To 172 mg of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-O(t-Bu) was added 0.3 mL of trifluoroacetic acid and 15 mL of water. The reaction mixture was left at 5° C. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography (45% EtOAc in hexane) to give 67 mg of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-OH as a gum at 45% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ7.88 (d, J=5 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 4.80 (dd14, J=21 Hz, 2H), 3.61 (t, J=7 Hz, 1H), 3.20 (m, 2H), 2.78 (m, 1H), 1.78 (m, 2H), 1.50 (m, 1H), 1.33 (d, J=7 Hz, 3H), 0.97 (d, J=6 Hz, 3H), 0.94 (d, J=6 Hz, 3H); [α]_(D) ²⁵ +126° (c=1.34, MeOH).

18B. Preparation of the Corresponding (S) Isomer of Formula 23

By following the procedure described in Example 18A and substituting the (R)-isomer with PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-Ot-Bu there is obtained PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-OH.

18C. Formula 23 Varying R²

By following the procedures described in Example 18A and substituting PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-O(t-Bu) with other compounds of Formula 22 there are obtained the correspondingly substituted compounds of Formula 23 (where R² and R³ are as indicated in the table below).

    __________________________________________________________________________     Formula 23                                                                      ##STR92##                                                                     where R.sup.3 is 2-methylpropyl                                                R.sup.2   Name                                                                 __________________________________________________________________________     hydrogen  PhtNCH.sub.2 SCH.sub.2 CH.sub.2 (SDLeu)OH                            2-propyl  PhtNCH.sub.2 SCH.sub.2 (R)CH(2-propyl)-(SDLeu)OH                     2-methylpropyl                                                                           PhtNCH.sub.2 SCH.sub.2 (R)CH(2-methylpropyl)-(SDLeu)OH               2-butyl   PhtNCH.sub.2 SCH.sub.2 (R)CH(2-butyl)-(SDLeu)OH                      blocked aminoethyl                                                                       PhtNCH.sub.2 SCH.sub.2 (R)CH(aminoethyl)-(SDLeu)OH                   blocked aminobutyl                                                                       PhtNCH.sub.2 SCH.sub.2 (R)CH(aminobutyl)-(SDLeu)OH                   carbamoylmethyl                                                                          PhtNCH.sub.2 SCH.sub.2 (R)CH(carbamoylmethyl)-(SDLeu)OH              __________________________________________________________________________

18D. Formula 23 Varying R²

By following the procedures described in Example 18B and substituting PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-O(t-Bu) with other compounds of Formula 22 there are obtained the correspondingly substituted compounds of Formula 23 (where R² and R³ are as indicated in the table below).

    __________________________________________________________________________     Formula 23                                                                      ##STR93##                                                                     where R.sup.3 is 2-methylpropyl                                                R.sup.2   Name                                                                 __________________________________________________________________________     2-propyl  PhtNCH.sub.2 SCH.sub.2 (S)CH(2-propyl)-(SDLeu)OH                     2-methylpropyl                                                                           PhtNCH.sub.2 SCH.sub.2 (S)CH(2-methylpropyl)-(SDLeu)OH               2-butyl   PhtNCH.sub.2 SCH.sub.2 (S)CH(2-butyl)-(SDLeu)OH                      blocked aminoethyl                                                                       PhtNCH.sub.2 SCH.sub.2 (S)CH(aminoethyl)-(SDLeu)OH                   blocked aminobutyl                                                                       PhtNCH.sub.2 SCH.sub.2 (S)CH(aminobutyl)-(SDLeu)OH                   carbamoylmethyl                                                                          PhtNCH.sub.2 SCH.sub.2 (S)CH(carbamoylmethyl)-(SDLeu)OH              __________________________________________________________________________

18E. Formula 23 Varying R² and R³

By following the procedures described in Example 18A and substituting PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-O(t-Bu) with other compounds of Formula 22 (e.g., compound prepared according to Examples 17A-17E) there are obtained the correspondingly substituted compounds of Formula 23 (where n, R² and R³ are as indicated in the table below).

    ______________________________________                                         Formula 23                                                                      ##STR94##                                                                     R.sup.2        R.sup.3                                                         ______________________________________                                         hydrogen       hydrogen                                                        2-propyl       methyl                                                          2-methylpropyl 2-propyl                                                        2-butyl        2-butyl                                                         blocked aminoethyl                                                                            2-methylpropyl                                                  blocked aminobutyl                                                                            blocked 4-hydroxyphenylmethyl                                   carbamoylmethyl                                                                               blocked 3-indolylmethyl                                         hydrogen       4-methoxyphenylmethyl                                           2-propyl       phenylethyl                                                     2-methylpropyl phenylethyl                                                     2-butyl        4-methoxyphenylmethyl                                           blocked aminoethyl                                                                            blocked 3-indolylmethyl                                         blocked aminobutyl                                                                            blocked 4-hydroxyphenylmethyl                                   carbamoylmethyl                                                                               2-methylpropyl                                                  hydrogen       2-butyl                                                         2-propyl       2-propyl                                                        2-methylpropyl methyl                                                          2-butyl        hydrogen                                                        blocked aminoethyl                                                                            hydrogen                                                        blocked aminobutyl                                                                            methyl                                                          carbamoylmethyl                                                                               2-propyl                                                        ______________________________________                                    

EXAMPLE 19 Preparation of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe

19A. Formula 24 Where R² Is Methyl, R³ Is 2-Methylpropyl, R⁴ Is Phenylmethyl, R⁵ Is Methyl

To a stirred solution of 67 mg of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-OH and 32 mg of PheNHMe in 2 mL of 1,2-dimethoxyethane were added 28 mg of 1-hydroxybenzotriazole and 43 mg of dicyclohexylcarbodiimideat 0°-5° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was evaporated and the residue was triturated with 15% CH₂ Cl₂ in hexane. The filtrate was dried over Na₂ SO₄ and evaporated under vacuum. Purification of the residue by flash chromatography (35% EtOAc in hexane) afforded 87 mg of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe as a solid: mp 86°-88° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.86 (d, J=6 Hz, 1H), 7.85 (d, J=6 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 6.10 (m, 1H), 4.98 (d, J=15 Hz, 1H), 4.71 (q, J=8 Hz, 1H), 4.63 (d, J=15 Hz, 1H), 3.54 (dd, J=6, 9 Hz, 1H), 2.88-3.18 (m, 4H), 2.74 (d, J=5 Hz, 3H), 2.42 (dd, J=11, 14 Hz, 1H), 1.66-1.78 (m, 1H), 1.45-1.53 (m, 1H), 1.26-1.38 (m, 1H 1.24 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 0.84 (d, J=6 Hz, 3H).

19B. Preparation of the Corresponding (S) Isomer of Formula 24

By following the procedure described in Example 1A and substituting the (R)-isomer with PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-OH there is obtained PhtNCH₂ SCH₂ (S) CHMe-(S-D-Leu)-Phe-NHMe.

19C. Formula 24 Varying R²

By following the procedures described in Example 19A and substituting PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-OH with other compounds of Formula 23 there are obtained the correspondingly substituted compounds of Formula 24 (where R², R³ R⁴, R⁵ and R⁶ are as indicated in the table below).

    __________________________________________________________________________     Formula 24                                                                      ##STR95##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.2   Name                                                                 __________________________________________________________________________     hydrogen  PhtNCH.sub.2 SCH.sub.2 CH.sub.2 (SDLeu)PheNHMe                       2-propyl  PhtNCH.sub.2 SCH.sub.2 (R)CH(2-propyl)-(SDLeu)PheNHMe                2-methylpropyl                                                                           PhtNCH.sub.2 SCH.sub.2 (R)CH(2-methylpropyl)-(SDLeu)PheNHMe          2-butyl   PhtNCH.sub.2 SCH.sub.2 (R)CH(2-butyl)-(SDLeu)PheNHMe                 blocked aminoethyl                                                                       PhtNCH.sub.2 SCH.sub.2 (R)CH(aminoethyl)-(SDLeu)PheNHMe              blocked aminobutyl                                                                       PhtNCH.sub.2 SCH.sub.2 (R)CH(aminobutyl)-(SDLeu)PheNHMe              carbamoylmethyl                                                                          PhtNCH.sub.2 SCH.sub.2 (R)CH(carbamoylmethyl)-(SDLeu)PheNHMe         __________________________________________________________________________

19D. Formula 24 Varying R²

By following the procedures described in Example 19B and substituting PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-OH with other compounds of Formula 23 there are obtained the correspondingly substituted compounds of Formula 24 (where R², R³, R⁴, R⁵ and R⁶ are as indicated in the table below).

    __________________________________________________________________________     Formula 24                                                                      ##STR96##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.2   Name                                                                 __________________________________________________________________________     2-propyl  PhtNCH.sub.2 SCH.sub.2 (S)CH(2-propyl)-(SDLeu)PheNHMe                2-methylpropyl                                                                           PhtNCH.sub.2 SCH.sub.2 (S)CH(2-methylpropyl)-(SDLeu)PheNHMe          2-butyl   PhtNCH.sub.2 SCH.sub.2 (S)CH(2-butyl)-(SDLeu)PheNHMe                 blocked aminoethyl                                                                       PhtNCH.sub.2 SCH.sub.2 (S)CH(aminoethyl)-(SDLeu)PheNHMe              blocked aminobutyl                                                                       PhtNCH.sub.2 SCH.sub.2 (S)CH(aminobutyl)-(SDLeu)PheNHMe              carbamoylmethyl                                                                          PhtNCH.sub.2 SCH.sub.2 (S)CH(carbamoylmethyl)-(SDLeu)PheNHMe         __________________________________________________________________________

19E. Formula 24 Varying n, R², R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 19A and substituting PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-OH with other compounds of Formula 23 (e.g., compounds with R² and R³) and PheNHMe with other compounds of Formula 6 (e.g., compounds with R⁴, R⁵ and R⁶) there are obtained the correspondingly substituted compounds of Formula 24 (where n, R², R³, R⁴, R⁵ and R⁶ are as indicated in the table below).

    __________________________________________________________________________     Formula 24                                                                      ##STR97##                                                                     where R.sup.5 is methyl or phenylmethyl                                        R.sup.2   R.sup.3     R.sup.4    R.sup.5                                       __________________________________________________________________________     hydrogen  hydrogen    phenylethyl                                                                               CH.sub.3                                      2-propyl  methyl      4-methoxyphenyl-                                                                          Bn                                                                  methyl                                                   2-methylpropyl                                                                           2-propyl    blocked 3- CH.sub.3                                                            indolylmethyl                                            2-butyl   2-butyl     blocked 4-hydroxy-                                                                        Bn                                                                  phenylmethyl                                             blocked aminoethyl                                                                       2-methylpropyl                                                                             benzyl     CH.sub.3                                      blocked aminobutyl                                                                       blocked 4-hydroxy-                                                                         blocked 4- Bn                                                      phenylmethyl                                                                               imidazoylmethyl                                          carbamoylmethyl                                                                          blocked 3-indolylmethyl                                                                    blocked 3- CH.sub.3                                                            guanylpropyl                                             hydrogen  4-methoxyphenylmethyl                                                                      blocked 4- Bn                                                                  aminobutyl                                               2-propyl  phenylethyl 2-methylpropyl                                                                            CH.sub.3                                      2-methylpropyl                                                                           phenylethyl 2-butyl    Bn                                            2-butyl   4-methoxyphenylmethyl                                                                      2-propyl   CH.sub.3                                      blocked aminoethyl                                                                       blocked 3-indolylmethyl                                                                    methyl     Bn                                            blocked aminobutyl                                                                       blocked 4-hydroxy-                                                                         hydrogen   CH.sub.3                                                phenylmethyl                                                         carbamoylmethyl                                                                          2-methylpropyl                                                                             hydrogen   Bn                                            hydrogen  2-butyl     methyl     CH.sub.3                                      2-propyl  2-propyl    2-propyl   Bn                                            2-methylpropyl                                                                           methyl      2-butyl    CH.sub.3                                      2-butyl   hydrogen    2-methylpropyl                                                                            Bn                                            blocked aminoethyl                                                                       hydrogen    blocked 4- CH.sub.3                                                            aminobutyl                                               blocked aminobutyl                                                                       methyl      blocked 3- Bn                                                                  guanylpropyl                                             carbamoylmethyl                                                                          2-propyl    2-butyl    Bn                                            __________________________________________________________________________

    __________________________________________________________________________     Formula 24                                                                      ##STR98##                                                                     where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.2  R.sup.3    R.sup.4  R.sup.6                                           __________________________________________________________________________     hydrogen hydrogen   phenylethyl                                                                             hydrogen                                          2-propyl methyl     4-methoxy-                                                                              2-propyl                                                              phenylmethyl                                               2-methylpropyl                                                                          2-propyl   blocked 3-                                                                              methyl                                                                indolylmethyl                                              2-butyl  2-butyl    blocked 4-                                                                              2-butyl                                                               hydroxyphenyl-                                                                 methyl                                                     blocked  2-methylpropyl                                                                            benzyl   2-methylpropyl                                    aminoethyl                                                                     blocked  blocked 4-hydroxy-                                                                        blocked 4-                                                                              blocked 4-                                        aminobutyl                                                                              phenylmethyl                                                                              imidazoylmethyl                                                                         aminobutyl                                        carbamoylmethyl                                                                         blocked 3-indolyl-                                                                        blocked 3-                                                                              blocked 3-                                                 methyl     guanylpropyl                                                                            guanylpropyl                                      hydrogen 4-         blocked 4-                                                                              2-imidazoyl-                                               methoxyphenylmethyl                                                                       aminobutyl                                                                              methyl                                            2-propyl phenylethyl                                                                               2-methylpropyl                                                                          hydroxymethyl                                     2-methylpropyl                                                                          phenylethyl                                                                               2-butyl  1-hydroxyethyl                                    2-butyl  4-         2-propyl thiolmethyl                                                methoxyphenylmethyl                                                   blocked  blocked 3-indolyl-                                                                        methyl   methylthio-                                       aminoethyl                                                                              methyl              ethyl                                             blocked  blocked 4-hydroxy-                                                                        hydrogen methylthio-                                       aminobutyl                                                                              phenylmethyl        ethyl                                             carbamoylmethyl                                                                         2-methylpropyl                                                                            hydrogen thiolmethyl                                       hydrogen 2-butyl    methyl   1-hydroxyethyl                                    2-propyl 2-propyl   2-propyl hydroxymethyl                                     2-methylpropyl                                                                          methyl     2-butyl  2-imidazoyl-                                                                   methyl                                            2-butyl  hydrogen   2-methylpropyl                                                                          blocked 3-                                                                     guanylpropyl                                      blocked  hydrogen   blocked 4-                                                                              blocked 4-                                        aminoethyl          aminobutyl                                                                              aminobutyl                                        blocked  methyl     blocked 3-                                                                              2-methylpropyl                                    aminobutyl          guanylpropyl                                               carbamoylmethyl                                                                         2-propyl   2-butyl  hydrogen                                          __________________________________________________________________________

EXAMPLE 20 Preparation of 2-NO₂ C₆ H₄ SSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe

20A. Formula 25 Where R² Is Methyl, R³ Is 2-Methylpropyl R⁴ Is Phenylmethyl, R⁵ Is Methyl

To a solution of 87 mg of PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe in 1 mL of acetic acid was added 34 mg of 2-NO₂ C₆ H₄ SCl. The mixture was stirred at room temperature for 17 h. The acetic acid was evaporated under vacuum and the residue was purified by flash chromatography (5% EtOAc in CH₂ Cl₂ ) to give mg of 2-NO₂ C₆ H₄ SSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe at 65% yield. Characteristic analytical data are as follows: ¹ H NMR (300 MHz, CDCl₃) δ8.27 (dd, J=1, 8 Hz, 1H), 8.23 (dd, J=1, 8 Hz, 1H), 7.69 (dr, J=l, 7 Hz, 1H), 7.21-7.39 (m, 6H), 6.98 (d, J=8 Hz, 1H), 6.10 (m, 1H), 4.57 (q, J=8 Hz, 1H), 3.19 (dd, J=6, 8 Hz, 1H), 3.10 (dd, J=7, 14 Hz, 1H), 3.04 (dd, J=8, 14 Hz, 1H), 2.83-2.92 (m, 1H), 2.73 (d, J=5 Hz, 3H), 2.60-2.70 (m, 2H), 1.52-1.69 (m, 2H), 1.40 H), 1.18 (d, J=7 Hz, 3H), 0.82 (d, J=7 Hz, 3H), 0.80 (d, J=7 Hz, 3H).

20B. Preparation of the Corresponding (S) Isomer of Formula 25

By following the procedure described in Example 20A and substituting the (R)-isomer with PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe there is obtained 2-NO₂ C₆ H₄ SSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe.

20C. Formula 25 Varying R²

By following the procedures described in Example 20A and substituting PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe with other compounds of Formula 24 there are obtained the correspondingly substituted compounds of Formula 25 (where R², R³, R⁴, R⁵ and R⁶ are as indicated in the table below).

    ______________________________________                                         Formula 25                                                                      ##STR99##                                                                     where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.2  Name                                                                  ______________________________________                                         hydrogen 2-NO.sub.2 C.sub.6 H.sub.4 SSCHCH.sub.2 (S-D-Leu)PheNHMe              2-propyl 2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (R)CH(2-propyl)-                         (S-D-Leu)PheNHMe                                                      2-methyl-                                                                               2-NO.sub.2 CH.sub.4 SSCH.sub.2 (R)CH(2-methylpropyl)-                 propyl   (S-D-Leu)PheNHMe                                                      2-butyl  2-NO.sub.2 CH.sub.4 SSCH.sub.2 (R)CH(2-butyl)-                                 (S-D-Leu)PheNHMe                                                      blocked  2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (R)CH(aminoethyl)-              aminoethyl                                                                              (S-D-Leu)PheNHMe                                                      blocked  2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (R)CH(aminobutyl)-              aminobutyl                                                                              (S-D-Leu)PheNHMe                                                      carbamoyl-                                                                              2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (R)CH(carbamoylmethyl)-         methyl   (S-D-Leu)PheNHMe                                                      PhtN-ethyl                                                                              2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (R)CH(PhtN-ethyl)-                       (S-D-Leu)PheNHMe                                                      PhtN-butyl                                                                              2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (R)CH(PhtN-butyl)-                       (S-D-Leu)PheNHMe                                                      ______________________________________                                    

20D. Formula 25 Varying R²

By following the procedures described in Example 20B and substituting PhtNCH₂ SCH₂ (S)CHMe-(S-D-Leu)-Phe-NHMe with other compounds of Formula 24 there are obtained the correspondingly substituted compounds of Formula 25 (where R², R³, R⁴, R⁵ and R⁶ are as indicated in the table below).

    ______________________________________                                         Formula 25                                                                      ##STR100##                                                                    where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.2     Name                                                               ______________________________________                                         2-propyl    2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (S)CH(2-propyl)-                         (S-D-Leu)PheNHMe                                                   2-methylpropyl                                                                             2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (S)CH(2-methylpropyl)-                   (S-D-Leu)PheNHMe                                                   2-butyl     2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (S)CH(2-butyl)-                          (S-D-Leu)PheNHMe                                                   blocked aminoethyl                                                                         2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (S)CH(aminoethyl)-                       (S-D-Leu)PheNHMe                                                   blocked aminobutyl                                                                         2-NO.sub.2 CH.sub.4 SSCH.sub.2 (S)CH(aminobutyl)-                              (S-D-Leu)PheNHMe                                                   carbamoylmethyl                                                                            2-NO.sub.2 CH.sub.4 SSCH.sub.2 (S)CH(carbamoylmethyl)-                         (S-D-Leu)PheNHMe                                                   PhtN-ethyl  2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (S)CH(PhtN-ethyl)-                       (S-D-Leu)PheNHMe                                                   PhtN-butyl  2-NO.sub.2 C.sub.6 H.sub.4 SSCH.sub.2 (S)CH(PhtN-butyl)-                       (S-D-Leu)PheNHMe                                                   ______________________________________                                    

20E. Formula 25 Varying n, R², R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 20A and substituting PhtNCH₂ SCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe with other compounds of Formula 24 (e.g., compound prepared according to Examples 19A-19E) there are obtained the correspondingly substituted compounds of Formula 25 (where n, R², R³, R⁴, R⁵ and R⁶ are as indicated in the tables below).

    ______________________________________                                         Formula 25                                                                      ##STR101##                                                                    where R.sup.5 is methyl or phenylmethyl                                        R.sup.2  R.sup.3       R.sup.4       R.sup.5                                   ______________________________________                                         hydrogen hydrogen      phenylethyl   CH.sub.3                                  2-propyl methyl        4-methoxyphenyl-                                                                             Bn                                                               methyl                                                  2-methyl-                                                                               2-propyl      blocked 3-    CH.sub.3                                  propyl                 indolylmethyl                                           2-butyl  2-butyl       blocked 4-hydroxy-                                                                           Bn                                                               phenylmethyl                                            blocked  2-methylpropyl                                                                               benzyl        CH.sub.3                                  aminoethyl                                                                     blocked  blocked 4-hydroxy-                                                                           blocked 4-    Bn                                        aminobutyl                                                                              phenylmethyl  imidazoylmethyl                                         carbamoyl-                                                                              blocked       blocked 3-    CH.sub.3                                  methyl   3-indolylmethyl                                                                              guanylpropyl                                            hydrogen 4-methoxyphenyl-                                                                             blocked 4-    Bn                                                 methyl        aminobutyl                                              2-propyl phenylethyl   2-methylpropyl                                                                               CH.sub.3                                  2-methyl-                                                                               phenylethyl   2-butyl       Bn                                        propyl                                                                         2-butyl  4-methoxyphenyl-                                                                             2-propyl      CH.sub.3                                           methyl                                                                blocked  blocked       methyl        Bn                                        aminoethyl                                                                              3-indolylmethyl                                                       blocked  blocked 4-hydroxy-                                                                           hydrogen      CH.sub.3                                  aminobutyl                                                                              phenylmethyl                                                          carbamoyl-                                                                              2-methylpropyl                                                                               hydrogen       Bn                                       methyl                                                                         hydrogen 2-butyl       methyl        CH.sub.3                                  2-propyl 2-propyl      2-propyl      Bn                                        2-methyl-                                                                               methyl        2-butyl       CH.sub.3                                  propyl                                                                         2-butyl  hydrogen      2-methylpropyl                                                                               Bn                                        blocked  hydrogen      blocked 4-    CH.sub.3                                  aminoethyl             aminobutyl                                              blocked  methyl        blocked 3-    Bn                                        aminobutyl             guanylpropyl                                            carbamoyl-                                                                              2-propyl      2-butyl       Bn                                        methyl                                                                         ______________________________________                                    

    ______________________________________                                         Formula 25                                                                      ##STR102##                                                                    where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.2  R.sup.3     R.sup.4     R.sup.6                                       ______________________________________                                         hydrogen hydrogen    phenylethyl hydrogen                                      2-propyl methyl      4-methoxy-  2-propyl                                                           phenylmethyl                                              2-methyl-                                                                               2-propyl    blocked 3-  methyl                                        propyl               indolylmethyl                                             2-butyl  2-butyl     blocked 4-  2-butyl                                                            hydroxyphenyl-                                                                 methyl                                                    blocked  2-methylpropyl                                                                             benzyl      2-methylpropyl                                aminoethyl                                                                     blocked  blocked 4-  blocked 4-  blocked 4-                                    aminobutyl                                                                              hydroxyphenyl-                                                                             imidazoyl-  aminobutyl                                             methyl      methyl                                                    carbamoyl-                                                                              blocked 3-  blocked 3-  blocked 3-                                    methyl   indolylmethyl                                                                              guanylpropyl                                                                               guanylpropyl                                  hydrogen 4-methoxy-  blocked 4-  2-imidazoyl-                                           phenylmethyl                                                                               aminobutyl  methyl                                        2-propyl phenylethyl 2-methylpropyl                                                                             hydroxymethyl                                 2-methyl-                                                                               phenylethyl 2-butyl     1-hydroxyethyl                                propyl                                                                         2-butyl  4-methoxy-  2-propyl    thiolmethyl                                            phenylmethyl                                                          blocked  blocked 3-  methyl      methylthio-                                   aminoethyl                                                                              indolylmethyl                                                                              ethyl                                                     blocked  blocked 4-  hydrogen    methylthio-                                   aminobutyl                                                                              hydroxyphenyl-                                                                             ethyl                                                              methyl                                                                carbamoyl-                                                                              2-methylpropyl                                                                             hydrogen    thiolmethyl                                   methyl                                                                         hydrogen 2-butyl     methyl      1-hydroxyethyl                                2-propyl 2-propyl    2-propyl    hydroxymethyl                                 2-methyl-                                                                               methyl      2-butyl     2-imidazoyl-                                  propyl                           methyl                                        2-butyl  hydrogen    2-methylpropyl                                                                             blocked 3-                                                                     guanylpropyl                                  blocked  hydrogen    blocked 4-  blocked 4-                                    aminoethyl           aminobutyl  aminobutyl                                    blocked  methyl      blocked 3-  2-methylpropyl                                aminobutyl           guanylpropyl                                              carbamoyl-                                                                              2-propyl    2-butyl     hydrogen                                      methyl                                                                         ______________________________________                                    

EXAMPLE 21 Preparation of HSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe

21A. Formula I Where R² Is Methyl, R³ Is 2-Methylpropyl, R⁴ Is Phenylmethyl, R⁵ Is Methyl

To a solution of 30 mg of 2-NO₂ C₆ H₄ SSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe in 0.4 mL of MeOH and 0.1 mL of dioxane was added 0.09 mL of 2-mercaptoethanol and 0.14 mL of 0.4M NaOH. The mixture was stirred at room temperature under nitrogen for 30 min, poured into water, acidified with acetic acid and extracted with CH₂ Cl₂. The organic layer was dried over Na₂ SO₄ and evaporated under vacuum. Purification of the residue by flash chromatography (25% EtOAc in hexane) afforded 12 mg of HSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe as a solid at 56% yield. Characteristic analytical data are as follows: mp 153°-155° C.; ¹ H NMR (300 MHz, CDCl₃) δ7.20-7.34 (m, 5H), 7.11 (d, J=8 Hz, 1H), 5.96 (m, 1H), 4.64 (q, J=8 Hz, 1H), 3.34 (dd, J= 6, 9 Hz, 1H), 3.14 (dd, J=7, 14 Hz, 1H), 3.08 (dd, J=8, 14 Hz, 1H), 2.75 (d, J=5 Hz, 3H), 2.64-2.73 (m, 1H), 2.44-2.60 (m, 2H), 1.40-1.72 (m, 3H), 1.53 (t, J=8 Hz, 1H, SH), 1.15 (d, J=7 Hz, 3H), 0.89 (d, J=7 Hz, 3H), 0.88 (d, J=7 Hz, 3H).

21B. Preparation of the Corresponding (S) Isomer of Formula I

By following the procedure described in Example 21A and substituting the (R)-isomer with 2-NO₂ C₆ H₄ SSCH₂ (S)CHMe-(S-D-Leu)-Phe-NHMe there is obtained HSCH₂ (S)CHMe-(S-D-Leu)-Phe-NHMe.

21C. Formula I Varying R²

By following the procedures described in Example 21A and substituting 2-NO₂ C₆ H₄ SSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe with other compounds of Formula 25 there are obtained the correspondingly substituted compounds of Formula I (where R², R³, R⁴, R⁵ and R⁶ are as indicated in the table below).

    ______________________________________                                         Formula I                                                                       ##STR103##                                                                    where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.2 Name                                                                   ______________________________________                                         hydrogen                                                                               HSCH.sub.2 CH.sub.2 (S-D-Leu)PheNHMe                                   2-propyl                                                                               HSCH.sub.2 (R)CH(2-propyl)-(S-D-Leu)PheNHMe                            2-methyl-                                                                              HSCH.sub.2 (R)CH(2-methylpropyl)-(S-D-Leu)                             propyl  PheNHMe                                                                2-butyl HSCH.sub.2 (R)CH(2-butyl)-(S-D-Leu)PheNHMe                             aminoethyl                                                                             HSCH.sub.2 (R)CH(aminoethyl)-(S-D-Leu)                                         PheNHMe                                                                aminobutyl                                                                             HSCH.sub.2 (R)CH(aminobutyl)-(S-D-Leu)                                         PheNHMe                                                                carbamoyl-                                                                             HSCH.sub.2 (R)CH(carbamoylmethyl)-(S-D-Leu)                            methyl  PheNHMe                                                                PhtN-ethyl                                                                             HSCH.sub.2 (R)CH(PhtN-ethyl)-(S-D-Leu)                                         PheNHMe                                                                PhtN-butyl                                                                             HSCH.sub.2 (R)CH(PhtN-butyl)-(S-D-Leu)                                         PheNHMe                                                                ______________________________________                                    

21D. Formula I Varying R²

By following the procedures described in Example 21B and substituting 2-NO₂ C₆ H₄ SSCH₂ (S)CHMe-(S-D-Leu)-Phe-NHMe with other compounds of Formula 25 there are obtained the correspondingly substituted compounds of Formula I (where R², R³, R⁴, R⁵ and R⁶ are as indicated in the table below).

    ______________________________________                                         Formula I                                                                       ##STR104##                                                                    where R.sup.3 is 2-methylpropyl, R.sup.4 is phenylmethyl,                      R.sup.5 is methyl                                                              R.sup.2 Name                                                                   ______________________________________                                         2-propyl                                                                               HSCH.sub.2 (S)CH(2-propyl)-(S-D-Leu)PheNHMe                            2-methyl-                                                                              HSCH.sub.2 (S)CH(2-methylpropyl)-(S-D-Leu)                             propyl  PheNHMe                                                                2-butyl HSCH.sub.2 (S)CH(2-butyl)-(S-D-Leu)PheNHMe                             aminoethyl                                                                             HSCH.sub.2 (S)CH(aminoethyl)-(S-D-Leu)                                         PheNHMe                                                                aminobutyl                                                                             HSCH.sub.2 (S)CH(aminobutyl)-(S-D-Leu)                                         PheNHMe                                                                carbamoyl-                                                                             HSCH.sub.2 (S)CH(carbamoylmethyl)-(S-D-Leu)                            methyl  PheNHMe                                                                PhtN-ethyl                                                                             HSCH.sub.2 (S)CH(PhtN-ethyl)-(S-D-Leu)                                         PheNHMe                                                                PhtN-butyl                                                                             HSCH.sub.2 (S)CH(PhtN-butyl)-(S-D-Leu)                                         PheNHMe                                                                ______________________________________                                    

21E. Formula I Varying R², R³, R⁴, R⁵ and R⁶

By following the procedures described in Example 21A and substituting 2-NO₂ C₆ H₄ SSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe with other compounds of Formula 25 (e.g., compounds prepared according to Examples 20A-20E) there are obtained the correspondingly substituted compounds of Formula I (where n, R², R³, R⁴, R⁵ and R⁶ are as indicated in the tables below).

    ______________________________________                                         Formula I                                                                       ##STR105##                                                                    where R.sup.5 is methyl or phenylmethyl                                        R.sup.2  R.sup.3       R.sup.4   R.sup.5                                       ______________________________________                                         hydrogen hydrogen      phenylethyl   CH.sub.3                                  2-propyl methyl        4-methoxyphenyl-                                                                             Bn                                                               methyl                                                  2-methyl-                                                                               2-propyl      3-indolylmethyl                                                                              CH.sub.3                                  propyl                                                                         2-butyl  2-butyl       4-hydroxyphenyl-                                                                             Bn                                                               methyl                                                  aminoethyl                                                                              2-methylpropyl                                                                               benzyl        CH.sub.3                                  aminobutyl                                                                              4-hydroxy-    4-imidazoylmethyl                                                phenylmethyl                                                          carbamoyl-                                                                              3-indolylmethyl                                                                              3-guanylpropyl                                          methyl                                                                         hydrogen 4-methoxy-    4-aminobutyl  Bn                                                 phenylmethyl                                                          2-propyl phenylethyl   2-methylpropyl                                                                               CH.sub.3                                  2-methyl-                                                                               phenylethyl   2-butyl       Bn                                        propyl                                                                         2-butyl  4-methoxy-    2-propyl      CH.sub.3                                           phenylmethyl                                                          aminoethyl                                                                              3-indolylmethyl                                                                              methyl                                                  aminobutyl                                                                              4-hydroxy-    hydrogen      CH.sub.3                                           phenylmethyl                                                          carbamoyl-                                                                              2-methylpropyl                                                                               hydrogen      Bn                                        methyl                                                                         hydrogen 2-butyl       methyl        CH.sub.3                                  2-propyl 2-propyl      2-propyl      Bn                                        2-methyl-                                                                               methyl        2-butyl       CH.sub.3                                  propyl                                                                         2-butyl  hydrogen      2-methylpropyl                                                                               Bn                                        aminoethyl                                                                              hydrogen      4-aminobutyl  CH.sub.3                                  aminobutyl                                                                              methyl        3-guanylpropyl                                                                               Bn                                        carbamoyl-                                                                              2-propyl      2-butyl       Bn                                        methyl                                                                         ______________________________________                                    

    ______________________________________                                         Formula I                                                                       ##STR106##                                                                    where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.2 R.sup.3      R.sup.4     R.sup.6                                       ______________________________________                                         hydrogen                                                                               hydrogen     phenylethyl hydrogen                                      2-propyl                                                                               methyl       4-methoxy-  2-propyl                                                           phenylmethyl                                              2-methyl-                                                                              2-propyl     3-indolylmethyl                                                                            methyl                                        propyl                                                                         2-butyl 2-butyl      4-hydroxy-  2-butyl                                                            methyl                                                    aminoethyl                                                                             2-methylpropyl                                                                              benzyl      2-methylpropyl                                aminobutyl                                                                             4-hydroxy-   4-imidazoyl-                                                                               4-aminobutyl                                          phenylmethyl methyl                                                    carbamoyl-                                                                             3-indolylmethyl                                                                             3-guanylpropyl                                                                             3-guanylpropyl                                methyl                                                                         hydrogen                                                                               4-methoxy-   4-aminobutyl                                                                               2-imidazoyl-                                          phenylmethyl             methyl                                        2-propyl                                                                               phenylethyl  2-methylpropyl                                                                             hydroxymethyl                                 2-methyl-                                                                              phenylethyl  2-butyl     1-hydroxyethyl                                propyl                                                                         2-butyl 4-methoxyphenyl-                                                                            2-propyl    thiolmethyl                                           methyl                                                                 aminoethyl                                                                             3-indolylmethyl                                                                             methyl      methylthio-                                                                    ethyl                                         aminobutyl                                                                             4-hydroxy-   hydrogen    methylthio-                                           phenylmethyl             ethyl                                         carbamoyl-                                                                             2-methylpropyl                                                                              hydrogen    thiomethyl                                    methyl                                                                         hydrogen                                                                               2-butyl      methyl      1-hydroxyethyl                                2-propyl                                                                               2-propyl     2-propyl    hydroxymethyl                                 2-methyl                                                                               methyl       2-butyl     2-imidazoyl-                                  propyl                           methyl                                        2-butyl hydrogen     2-methylpropyl                                                                             3-guanylpropyl                                aminoethyl                                                                             hydrogen     4-aminobutyl                                                                               4-aminobutyl                                  aminobutyl                                                                             methyl       3-guanylpropyl                                                                             2-methylpropyl                                carbamoyl-                                                                             2-propyl     2-butyl     hydrogen                                      methyl                                                                         ______________________________________                                    

EXAMPLE 22

22A. Preparation of Formula 6

1. Formula 6 Where R⁴ Is Phenylmethyl and R⁵ Is --CH(R⁶)--C(O)NH₂ Where R⁶ Is Methyl

The following procedure for the preparation of the amino acid residue is a modification of the procedures reported in Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis; Springer-Verlag: New York, 1984; p 129-142. A mixture of 5.00 g of Cbz-Phe-OH (Sigma Chemical Company), 2.12 g of N-hydroxysuccinimide and 3.79 g of 1,3-dicyclohexylcarbodiimide in 20 mL of dry THF was kept at 4° C. under N₂ for 26 h. The resulting precipitate was removed by filtration. To the filtrate was added an aqueous solution of 1.79 g of Ala-OH containing 0.802 g of NaOH. The mixture was stirred at room temperature for 18 h. The solid was removed by filtration and the filtrate was diluted with saturated aqueous NaHCO₃ and extracted with CHCl₃. The aqueous layer was acidified with 1M HCl and the resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 6.00 g (97% yield) of Cbz-Phe-Ala-OH, which was used without further purification. Characteristic analytical data are as follows: mp 153°-154° C.; ¹ H NMR (300 MHz, CDCl₃ --CD₃ OD) δ7.38-7.10 (m, 10H, 2×Ph), 6.91-6.80 (br, 1H, H--N), 5.60-5.52 (br, 1H, H--N), 5.03 (s, 2H, CH₂ -Bn), 4.45-4.38 (m, 2H, Hα-(Phe)+Hα-(Ala)), 3.01 (m, 2H, CH₂ -(Phe)), 1.35 (d, J=7 Hz, 3H, CH₃ -(Ala)).

The above described procedure was repeated using 5.65 g of Cbz-Phe-Ala-OH and excess anhydrous ammonia in THF to obtain 7.16 g of crude Cbz-Phe-Ala-NH₂. The crude product was then subjected to hydrogenolysis in MeOH over 10% Pd/C to afford 3.42 g (95% yield) of Phe-Ala-NH₂ as a yellow solid after flash chromatography (EtOAc-MeOH, 10:1). Characteristic analytical data are as follows: mp 95°-97° C.; R_(F) 0.10 (1:2 MeOH:EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ7.80-7.72 (br, 1H, H--N), 7.35-7.18 (m, 5H, Ph), 6.58-6.45 (br, 1H, H--N), 5.70-5.60 (br, 1H, H--N), 4.46 (quint, J=7 Hz, 1H, Hα-(Ala)), 3.62 (dd, J=4, 9 Hz, 1H, Hα-(Phe)), 3.21 (dd, J=4, 11 Hz, 1H, Hβ-(Phe)), 2.72 (dd, J=9, 11 Hz, 1H, Hβ-(Phe)), 1.35 (d, J=7 Hz, 3H, CH₃); ¹³ C NMR (75 MHz, CDCl₃) δ175.3 (C═O), 174.8 (C═O), 137.6 (C-Ph), 129.4 (CH-Ph), 128.8 (CH-Ph), 127.0 (CH-Ph), 56.0 (CH-α), 48.0 (CH-α), 40.5 (CH₂), 17.7 (CH₃); [α]_(D) ²⁵ -25.6° (C=1.90, EtOH).

2. Formula 6 Where R⁴ Is 3-indolylmethyl and R⁵ Is Phenylmethyl

The coupling procedure described above for the preparation of Cbz-Phe-Ala-NH₂ was employed using 10.0 g of Cbz-Trp-OH (Sigma Chemical Company) and 4.84 mL of freshly distilled BnNH₂ in dry THF to give 11.3 g (89% yield) of crystalline Cbz-Trp-NHBn. Characteristic analytical data are as follows: mp 104°-105° C.; ¹ H NMR (300 MHz, CDCl₃) δ8.00-6.88 (m, 16H, Ar), 5.85 (br, 1H, H-α), 5.45 (br, 1H, H--N), 5.10 (s, 2H, CH₂ --O), 4.57-4.45 (br, H--), 4.27 (t, 6H, CH₂ --N), 3.38 (dd, J=4, 14 Hz, 1H, H-β), 3.16 (dd, J=8, 14 Hz, 1H, H-β); mass spectrum (EI), m/e 427 (M⁺), 336 (M⁺ -Bn), 277 (M⁺ -Cbz-NH), 130 (M³⁰ -Cbz-NH--CH--CONH-Bn), 91 (Bn⁺); [α]_(D) ²⁵ +7.0° (c=0.20, EtOAc).

A solution of 2.20 g (5.15 mmol) Cbz-Trp-NHBn in 60 mL of MeOH was subjected to hydrogenolysis over Pd/C to give 1.43 g (4.88 mmol, 95%) of Trp-NHBn. Characteristic analytical data are as follows: mp 112°-114° C.; ¹ H NMR (300 MHz, CDCl₃) δ8.40-7.00 (m, 11H, Ar), 4.44 (d, J=6 Hz, 2H, CH₂ --N), 3.77 (dd, J=4 Hz, 9H, H-α), 3.42 (dd, J=4, 14 Hz, 1H, H-β), 2.98 (dd, J=9, 14 Hz, 1H, H-β); mass spectrum (EI), m/e 293 (M⁺), 277 (M⁺ -NH₂), 130 (M⁺ -H₂ N--CH--CONH-Bn); [α]_(D) ²⁵ +42.1° (c=1.02, MeOH).

3. Formula 6 Where R⁴ Is Phenylmethyl and R⁵ Is Methyl

A mixture of 1.00 g of Cbz-Phe-OH (Sigma Chemical Company), 0.385 g of N-hydroxysuccinimide and 0.541 g of 1,3-dicyclohexylcarbodiimide in 5 mL of dry THF was kept at 4° C. under N₂ overnight. The resulting precipitate was removed by filtration, and to the filtrate was added excess 40% aqueous methylamine at room temperature. The mixture was stirred at room temperature for 30 min. The solid was removed by filtration and the filtrate was partitioned between saturated aqueous NaHCO₃ and CH₂ Cl₂. The organic layer was separated, dried over anhydrous Na₂ SO₄, and evaporated under reduced pressure to give 1.12 g of the crude Cbz-Phe-NHMe.

To a solution of the crude product in 30 mL of MeOH was added 0.21 g of 10% Pd/C and H₂ was bubbled through the mixture via a dispersion tube until TLC analysis showed completion of the hydrogenolysis (3 h). The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was partitioned between CHCl₃ and water and the aqueous layer was acidified with 1M HCl to approximately pH 2 and was extracted with CHCl₃ (3×). The aqueous layer was then neutralized with 10% NaOH and again was extracted with CHCl₃ (3×). The latter organic extract was dried over anhydrous Na₂ SO₄ and was evaporated under reduced pressure to give 0.554 g (93% yield) of Phe-NHMe. Characteristic analytical data are as follows: mp 48°-50° C.; R_(F) 0.10 (EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ7.34-7.20 (m, 5H, Ph), 3.60 (dd, J=4, 9 Hz, 1H, H-α), 3.30 (dd, J=4, 11 Hz, 1H, H-β), 2.81 (d, 5H, CH₃ --N), 2.65 (dd, J=9, 11 Hz, 1H, H-β); ¹³ C NMR (75 MHz, CDCl₃) δ175.6 (C═O), 138.6 (C-Ph), 129.9 (CH-Ph), 129.3 (CH-Ph), 127.3 (CH-Ph), 56.8 (CH₃), 41.3 (CH), 26.0 (CH₂); mass spectrum (PCI), m/e 179 (M+1); [α]_(D) ²⁵ +8.5° (c=4.20, EtOH).

5B. Formula 6 Varying R⁴, R⁵ and R⁶

By following the procedures described in Example 5A and substituting CBz-Phe-OH and Ala-OH with other compounds of Formulae 6A and 6B, respectively [where the substituents R⁴ (Formula 6A), and R⁵ and R⁶ (Formula 6B) are as indicated in the table below] there are obtained the correspondingly substituted compounds of Formula 6.

    ______________________________________                                         Formula 6                                                                       ##STR107##                                                                    where R.sup.5 is methyl or phenylmethyl                                        R.sup.4            R.sup.5 Name                                                ______________________________________                                         hydrogen           CH.sub.3                                                                               GlyCH.sub.3                                         methyl             Bn      AlaBn                                               2-propyl           CH.sub.3                                                                               ValCH.sub.3                                         2-butyl            Bn      LeuBn                                               2-methylpropyl     CH.sub.3                                                                               IleCH.sub.3                                         blocked 4-aminobutyl                                                                              Bn      LysBn                                               blocked 3-guanylpropyl                                                                            CH.sub.3                                                                               ArgCH.sub.3                                         blocked 4-imidazoylmethyl                                                                         Bn      HisBn                                               benzyl             CH.sub.3                                                                               PheCH.sub.3                                         blocked 4-hydroxyphenylmethyl                                                                     Bn      TyrBn                                               blocked 3-indolylmethyl                                                                           CH.sub.3                                                                               TrpCH.sub.3                                         4-methoxyphenylmethyl                                                                             Bn      (TyrOCH.sub.3)Bn                                    phenylethyl        CH.sub.3                                                                               (Phet)CH.sub.3                                      ______________________________________                                    

    ______________________________________                                         Formula 6                                                                       ##STR108##                                                                    where R.sup.5 is CH(R.sup.6)C(O)NH.sub.2                                       R.sup.4    R.sup.6     Name                                                    ______________________________________                                         hydrogen   methyl      GlyAlaNH.sub.2                                          methyl     2-butyl     AlaIleNH.sub.2                                          2-propyl   2-methylpropyl                                                                             ValLeuNH.sub.2                                          2-butyl    hydrogen    LeuGlyNH.sub.2                                          2-methylpropyl                                                                            2-propyl    IleValNH.sub.2                                          blocked    2-methylpropyl                                                                             LysLeuNH.sub.2                                          4-aminobutyl                                                                   blocked    methyl      ArgAlaNH.sub.2                                          3-guanylpropyl                                                                 blocked    2-butyl     HisIleNH.sub.2                                          4-imidazoylmethyl                                                              benzyl     2-methylpropyl                                                                             PheLeuNH.sub.2                                          blocked 4- hydrogen    TyrGlyNH.sub.2                                          hydroxyphenyl-                                                                 methyl                                                                         blocked    2-propyl    TrpValNH.sub.2                                          3-indolylmethyl                                                                4-methoxy- 2-methylpropyl                                                                             (TyrOCH.sub.3)LeuNH.sub.2                               phenylmethyl                                                                   phenylethyl                                                                               methyl      (Phet)AlaNH.sub.2                                       hydrogen   blocked     GlyLysNH.sub.2                                                     4-aminobutyl                                                        methyl     blocked 3-  AlaArgNH.sub.2                                                     guanylpropyl                                                        2-propyl   2-imidazoyl-                                                                               ValHisNH.sub.2                                                     methyl                                                              2-butyl    blocked     LeuLysNH.sub.2                                                     4-aminobutyl                                                        2-methylpropyl                                                                            blocked 3-  IleArgNH.sub.2                                                     guanylpropyl                                                        blocked    2-imidazoyl-                                                                               LysHisNH.sub.2                                          4-aminobutyl                                                                              methyl                                                              blocked    blocked     ArgLysNH.sub.2                                          3-guanylpropyl                                                                            4-aminobutyl                                                        blocked    blocked 3-  HisArgNH.sub.2                                          4-imidazoylmethyl                                                                         guanylpropyl                                                        benzyl     2-imidazoyl-                                                                               PheHisNH.sub.2                                                     methyl                                                              blocked    blocked     TyrLysNH.sub.2                                          4-hydroxy- 4-aminobutyl                                                        phenylmethyl                                                                   blocked    blocked 3-  TrpArgNH.sub.2                                          3-indolylmethyl                                                                           guanylpropyl                                                        4-methoxy- 2-imidazoyl-                                                                               (TyrOCH.sub.3)HisNH.sub.2                               phenylmethyl                                                                              methyl                                                              phenylethyl                                                                               blocked     (Phet)LysNH.sub.2                                                  4-aminobutyl                                                        hydrogen   thiolmethyl GlyCysNH.sub.2                                          methyl     methylthioethyl                                                                            AlaMetNH.sub.2                                          2-propyl   hydroxymethyl                                                                              ValSerNH.sub.2                                          2-butyl    1-hydroxyethyl                                                                             LeuThrNH.sub.2                                          2-methylpropyl                                                                            thiolmethyl IleCysNH.sub.2                                          blocked    methylthioethyl                                                                            LysMetNH.sub.2                                          4-aminobutyl                                                                   blocked    hydroxymethyl                                                                              ArgSerNH.sub.2                                          3-guanylpropyl                                                                 blocked    1-hydroxyethyl                                                                             HisThrNH.sub.2                                          4-imidazoylmethyl                                                              benzyl     thiolmethyl PheCysNH.sub.2                                          blocked    methylthioethyl                                                                            TyrMetNH.sub.2                                          4-hydroxy-                                                                     phenylmethyl                                                                   blocked    hydroxymethyl                                                                              TrpSerNH.sub.2                                          3-indolylmethyl                                                                4-methoxy- 1-hydroxyethyl                                                                             (TyrOCH.sub.3)ThrNH.sub.2                               phenylmethyl                                                                   phenylethyl                                                                               hydroxymethyl                                                                              (Phet)SerNH.sub.2                                       blocked    methylthioethyl                                                                            ArgMetNH.sub.2                                          3-guanylpropyl                                                                 ______________________________________                                    

EXAMPLE 23 Determination of Fibroblast Collagenase (HFC) Inhibition

Starting Materials and Reagents

Pro-HFC was purified from the harvest media of human gingival fibroblasts following procedures described in Birkedal-Hansen, H. Methods Enzymol. 1987, 144, 140-171.

The HFC used in the assays was either zymogen that had undergone spontaneous activation, or zymogen that had been activated by treatment with 100 μg/mL of trypsin for 15 min at 23° C., followed by the addition of a 4-fold excess of soybean trypsin inhibitor.

Kinetic Measurements

Assays were performed in 50 mM Tricine, 0.2M NaCl, 10 mM CaCl₂, pH 7.5 containing 5% methanol once the substrate and inhibitor were diluted into it. The buffer was freed from adventitious metal ions by extraction with dithizone in carbon tetrachloride (Holmquist, B. Methods Enzymol. 1988, 158, 6-10). Stock solutions of inhibitors were prepared in 100% methanol. The concentrations of the stock solutions of sulfhydryl-containing inhibitors were determined spectrophotometrically by reaction with Ellman's reagent (Riddles, P. W.; Blakeley, R. L.; Zerner, B. Anal. Biochem. 1979, 94, 75-81) immediately prior to their use. Stock solutions of the substrate were prepared in 50% aqueous methanol at a concentration of 0.2 mM.

The assay method used was based on the hydrolysis of DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg at 24° C. (Netzel-Arnett, S.; Mallya, S. K.; Nagase, H.; Birkedal-Hansen, H.; Van Wart, H. E. Anal. Biochem. 1991, 195, 86-92). The fluorescence changes were monitored with a Perkin-Elmer Model LS-5 fluorometer using an excitation wavelength of 280 nm and an emission wavelength of 360 nm. The substrate concentration used in the assays was either 5 μM or 10 μM. The inhibitor was diluted into the assays using 100% methanol, and controls substituted an equal volume of methanol so that the final methanol concentration from inhibitor and substrate dilutions in all assays was 5%. For each assay, the enzyme and inhibitor were incubated in the assay buffer at 24° C. for 30 min, then the substrate was added and the rate of hydrolysis was measured by monitoring the increase in fluorescence intensity at 360 nm over a period of approximately 30 min. The inhibition results are expressed as the inhibitor concentration that produced 50 % inhibition (IC₅₀) of activity at the substrate concentration used.

Representative compounds of the present invention exhibited inhibition of HFC when tested by this method.

EXAMPLE 23 Determination of Neutrophil Collagenase (NHC) Inhibition

Starting Materials and Reagents

HNC (58 kDa active form) was isolated from human buffy coats following procedures described in Mookhtiar, K. A.; Van Wart, H. E. Biochemistry 1990, 29, 10620-10627.

HNC was isolated in active form and no additional treatments were performed before use in assays.

Kinetic Measurements

The preparation of enzyme, inhibitor and substrate solutions; and the assay method were performed using the procedure described in Example 21 (Kinetic Measurements Section).

Representative compounds of the present invention exhibited inhibition of HNC when tested by this method.

EXAMPLE 24 Determination of Fibroblast Gelatinase (HFG) Inhibition

Starting Materials and Reagents

Pro-HFG was purified from the harvest media of human gingival fibroblasts following procedures described in Birkedal-Hansen, H. Methods Enzymol. 1987, 144, 140-171.

Spontaneously activated HFG was used without additional treatment.

Kinetic Measurements

The preparation of enzyme, inhibitor and substrate solutions; and the assay method were performed using the procedure described in Example 21 (Kinetic Measurements Section).

Representative compounds of the present invention exhibited inhibition of HFG when tested by this method.

EXAMPLE 25 Determination of Neutrophil Gelatinase (HNG) Inhibition

Starting Materials and Reagents

Pro-HNG was isolated from human buffy coats following procedures described in Mookhtiar, K. A.; Van Wart, H. E. Biochemistry 1990, 29, 10620-10627.

Spontaneously activated HNG was used without additional treatment.

Kinetic Measurements

The preparation of enzyme, inhibitor and substrate solutions; and the assay method were performed using the procedure described in Example 21 (Kinetic Measurements Section).

Representative compounds of the present invention exhibited inhibition of HNG when tested by this method.

EXAMPLE 26 Determination of Stromelysin (HFS) Inhibition

Starting Materials and Reagents

Pro-HFS was isolated from the culture medium of human rheumatoid synovial cells stimulated with rabbit macrophage-conditioned medium by affinity chromatography using sheep anti-HFS IgG coupled to Affi-Gel 10 following procedures described in Ito, A.; Nagase, H. Arch. Biochem. Biophys. 1988, 267, 211-216.

Pro-HFS was activated by treatment with 1 mM p-aminophenylmercuric acetate (APMA) for 24 hr at 37° C. to give a mixture of 45 and 28 kDa species, which are known to have indistinguishable specific activities and specificities (following procedures described in Okada, Y.; Nagase, H.; Harris, E. D., Jr. J. Biol. Chem. 1986, 261, 14245-14255). HFS was separated from the APMA by chromatography over Sephacryl S-200 and it was stored at 4° C.

Kinetic Measurements

The preparation of enzyme, inhibitor and substrate solutions; and the assay method were performed using the procedure described in Example 21 (Kinetic Measurements Section).

Representative compounds of the present invention exhibited inhibition of HFS when tested by this method.

EXAMPLE 27 Determination of Matrilysin (PUMP) Inhibition

Starting Materials and Reagents

Pro-PUMP was isolated from Chinese hamster ovary cells carrying an amplified pro-PUMP cDNA (Yuan et al., in preparation). Briefly, conditioned medium was collected from cells grown in serum-free medium, concentrated, applied to a blue-Sepharose column and eluted in 20 mM Tris, 5 mM CaCl₂, 0.05% Brij-35, pH 7.4 with a 0-1.5M NaCl gradient. Fractions containing pro-PUMP were pooled and loaded directly onto a zinc-Sepharose column, and eluted with a 0-600 mM glycine gradient. The final purification was achieved by chromatography over S-Sepharose using a linear 0-1M NaCl gradient for elution.

Pro-PUMP was activated by treatment with 1 mM PCMB for 2 hr at 37° C. and then dialyzed against 50 mM Tricine, 0.2M NaCl, 10 mM CaCl₂, 50 μM ZnSO₄, 0.05% Brij-35, pH 7.5 to remove all traces of PCMB.

Kinetic Measurements

The preparation of enzyme, inhibitor and substrate solutions; and the assay method were performed using the procedure described in Example 21 (Kinetic Measurements Section).

Representative compounds of the present invention exhibited inhibition of PUMP when tested by this method.

EXAMPLE 28 Capsule Formulation

This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound of Formula I, e.g. , HS(CH₂)₂ --(S-D-Leu)-Phe-NHMe.

    ______________________________________                                         Ingredients    Quantity (mg/capsule)                                           ______________________________________                                         Active compound                                                                               200                                                             lactose, spray-dried                                                                          148                                                             magnesium stearate                                                                             2                                                              ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

Other compounds of Formula I, such as those prepared in accordance with Reaction Schemes A, B and C, and Examples 1-22 can be used as the active compound in the preparation of the orally administrable formulations of this example.

EXAMPLE 29 Oral Formulation

This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., HSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe.

An suspension for oral administration is prepared having the following composition:

    ______________________________________                                         Ingredients          Quantity                                                  ______________________________________                                         Active compound      1.0       g                                               fumaric acid         0.5       g                                               sodium chloride      2.0       g                                               methyl paraben       0.1       g                                               granulated sugar     25.5      g                                               sorbitol (70% solution)                                                                             12.85     g                                               Veegum K (Vanderbilt Co.)                                                                           1.0       g                                               flavoring            0.035     mL                                              colorings            0.5       mg                                              distilled water      q.s. to 100                                                                              mL                                              ______________________________________                                    

Other compounds of Formula I, such as those prepared in accordance with Reaction Schemes A, B and C, and Examples 1-22 can be used as the active compound in the preparation of the orally administrable formulations of this example.

EXAMPLE 30 Tablet Formulation

This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., HS(R)CHMeCH₂ -(S-D-Leu)-Phe-NHMe.

A tablet for oral administration is prepared having the following composition:

    ______________________________________                                         Ingredients    Quantity (mg/tablet)                                            ______________________________________                                         Active compound                                                                               400                                                             corn starch     50                                                             lactose        145                                                             magnesium stearate                                                                             5                                                              ______________________________________                                    

The above ingredients are mixed intimately and pressed into single scored tablets.

Other compounds of Formula I, such as those prepared in accordance with Reaction Schemes A, B and C, and Examples 1-22 can be used as the active compound in the preparation of the tablet formulations of this example.

EXAMPLE 31 Injectable Formulation

This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., HS(CH₂)₂ --(S-D-Leu)-Phe-NHMe.

An injectable preparation is prepared having the following composition:

    ______________________________________                                         Ingredients       Quantity                                                     ______________________________________                                         Active compound   0.2 g                                                        water (distilled, sterile)                                                                       q.s. to 20.0 mL                                              ______________________________________                                    

Other compounds of Formula I, such as those prepared in accordance with Reaction Schemes A, B and C, and Examples 1-22 can be used as the active compound in the preparation of the injection administrable formulations of this example.

EXAMPLE 32 Suppository Formulation

This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., HSCH₂ (R)CHMe-(S-D-Leu)-Phe-NHMe.

A suppository totalling 2.5 grams is prepared having the following composition:

    ______________________________________                                         Ingredients     Quantity                                                       ______________________________________                                         Active compound 500 mg                                                         witepsol H-15*  q.s. to 2.5 g                                                  ______________________________________                                          (*triglycerides of saturated vegatable fatty acid; a product of                RichesNelson, Inc., New York, N.Y.).                                     

Other compounds of Formula I, such as those prepared in accordance with Reaction Schemes A, B and C, and Examples 1-22 can be used as the active compound in the preparation of the suppository formulations of this example.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. 

What is claimed is:
 1. A compound of the formula, ##STR109## wherein: n is 0 or 1;R¹ is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); and R² is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); or R¹ and R² together are --CH₂ --CH₂ --CH₂ --; R³ is selected from the group consisting of hydrogen, lower alkyl, aralkyl and heteroaralkyl; and R⁴ is selected from the group consisting of hydrogen, lower alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, aralkyl and 2-indolylmethyl; and R⁵ is selected from the group consisting of lower alkyl, aralkyl and --CH(R⁶)--C(O)NH₂, whereinR⁶ is selected from the group consisting of hydrogen, lower-alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, hydroxymethyl, 1-hydroxyethyl, mercapto lower-alkyl, and methylthio lower-alkyl;or a pharmaceutically acceptable ester, ether or salt thereof.
 2. The compound of claim 1 wherein n is
 0. 3. The compound of claim 2 wherein R³ is lower-alkyl.
 4. The compound of claim 3 wherein the carbon that is the point of attachment for R³ is in the D-configuration.
 5. The compound of claim 4 wherein R³ is 2-methylpropyl.
 6. The compound of claim 5 wherein R⁴ is aralkyl.
 7. The compound of claim 6 wherein R⁴ is phenylmethyl.
 8. The compound of claim 6 wherein R⁵ is lower-alkyl.
 9. The compound of claim 8 wherein R⁵ is methyl.
 10. The compound of claim 6 wherein R⁵ is aralkyl.
 11. The compound of claim 10 wherein R⁵ is phenylmethyl.
 12. The compound of claim 6 wherein R⁵ is --CH(R⁶) --C(O)NH₂.
 13. The compound of claim 12 wherein R⁶ is lower alkyl.
 14. The compound of claim 12 wherein R⁶ is methyl.
 15. The compound of claim 12 wherein R¹ and R² together are --CH₂ --CH₂ --CH₂.
 16. The compound of claim 12 wherein R² is hydrogen.
 17. The compound of claim 16 wherein R¹ is selected from the group consisting of hydrogen, lower alkyl and PhtN(lower alkyl).
 18. The compound of claim 17 wherein R¹ is hydrogen.
 19. The compound of claim 17 wherein R¹ is methyl.
 20. The compound of claim 17 wherein R¹ is PhtNBu.
 21. The compound of claim 17 wherein R¹ is PhtNEt.
 22. The compound of claim 1 wherein n is
 1. 23. The compound of claim 22 wherein R³ is lower-alkyl.
 24. The compound of claim 23 wherein the carbon that is the point of attachment for R³ is in the D-configuration.
 25. The compound of claim 24 wherein R³ is 2-methylpropyl.
 26. The compound of claim 25 wherein R⁴ is aralkyl.
 27. The compound of claim 26 wherein R⁴ is phenylmethyl.
 28. The compound of claim 26 wherein R⁵ is lower alkyl.
 29. The compound of claim 28 wherein R⁵ is methyl.
 30. The compound of claim 26 wherein R⁵ is aralkyl.
 31. The compound of claim 30 wherein R⁵ is phenylmethyl.
 32. The compound of claim 26 wherein R⁵ is --CH(R⁶)--C(O)NH₂.
 33. The compound of claim 32 wherein R⁶ is lower alkyl.
 34. The compound of claim 33 wherein R⁶ is methyl.
 35. The compound of claim 1 that is HS(CH₃)₂ --(S-D-Leu)-Phe-NHMe.
 36. The compound of claim 1 that is HS(S)CHMeCH₂ --(S-D-Leu)-Phe-NHMe.
 37. The compound of claim 1 that is HS(S)CH(PhtNBu)CH₂ --(S-D-Leu)-Phe-NHMe.
 38. The compound of claim 1 that is HS(S)CH(PhtNEt)CH₂ --(S-D-Leu)-Phe-NHMe.
 39. The compound of claim 1 that is HS(1,2-cyclopentyl)(S-D-Leu)-Phe-NHMe.
 40. A compound of the formula, ##STR110## wherein: n is 0 or 1;R¹ is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); and R² is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); or R¹ and R² together are --CH₂ --CH₂ --CH₂ --; R³ is selected from the group consisting of hydrogen, lower alkyl, aralkyl and heteroaralkyl; and R⁴ is selected from the group consisting of hydrogen, lower alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, aralkyl and 2-indolylmethyl; and R⁵ is selected from the group consisting of lower alkyl, aralkyl and --CH(R⁶)--C(O)NH₂, whereinR⁶ is selected from the group consisting of hydrogen, lower-alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, hydroxymethyl, 1-hydroxyethyl, mercapto lower-alkyl, and methylthio lower-alkyl; ora pharmaceutically acceptable ester, ether or salt thereof used for inhibiting metalloproteinase activity.
 41. A pharmaceutical composition comprising a compound of the formula ##STR111## wherein: n is 0 or 1;R¹ is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); and R² is selected from the group consisting of hydrogen, lower alkyl, amino lower alkyl, carbamoyl lower alkyl, PhtN(lower alkyl), TsNH(lower alkyl); or R¹ and R² together are --CH₂ --CH₂ --CH₂ --; R³ is selected from the group consisting of hydrogen, lower alkyl, aralkyl and heteroaralkyl; and R⁴ is selected from the group consisting of hydrogen, lower alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, aralkyl and 2-indolylmethyl; and R⁵ is selected from the group consisting of lower alkyl, aralkyl and --CH(R⁶)--C(O)NH₂, whereinR⁶ is selected from the group consisting of hydrogen, lower-alkyl, amino lower-alkyl, guanyl lower-alkyl, imidazoylalkyl, hydroxymethyl, 1-hydroxyethyl, mercapto lower-alkyl, and methylthio lower-alkyl;or a pharmaceutically acceptable ester, ether or salt thereof and pharmaceutically acceptable excipients useful for modulating physiological functions or treating diseases and disease conditions associated with matrix metalloproteinase modulation. 